eFMC
`
`Riot Just Product; Part:1en"_:-f
`
`Aviceli RC—591
`Microcrystalline Cellulose and
`Carboxymethyloellulose Sodium, NF, BP
`
`Pharmaceutical Emulsions
`and Suspensions
`Stabilization Technology For Liquid
`And Semi-Solid Dosage Forms
`
`000001
`
`Exhibit 1 05 4
`
`IPR2017-00807
`
`Exhibit 1054
`IPR2017-00807
`ARGENTUM
`
`ARGENTUM
`
`000001
`
`

`

`AviceI® RC-591
`
`Microcrystalline Cellulose, NF, BP
`
`Ari:-of RG59! emulsion
`
`.
`‘u
`IL. ~" "
`L11
`Cullulon mlcmcryilals Ind ctyslnlmt aggrvgnfu
`
`Contents
`Pa 6
`Formulation Advantages...................................."'3
`Avicel RC-591 Overview .................................... ..3
`Structure and Function ...................................... ..4
`
`Rheological Properties ....................................... ..5
`Suspension Fonnulations
`Dispersion Factors
`Microscopic Features.........................................10
`Emulsion Stabilization ...................................... ..11
`
`Dispersion Procedures ..................................... ..13
`Dispersion Methods ......................................... ..16
`Product Summary ............................................ ..18
`
`1
`000002
`
`000002
`
`

`

`Advantages of formulating suspensions and
`emulsions with Avice|® RC-591
`
`I Viscosity regulator
`and modifier
`I Thixotrop_ic_
`Ch3'3Ct9”3t'C3
`- Heat and freeze—thaw
`stable
`
`I Long shelf-life stability
`
`0 Lengthy hydration
`times eliminated
`0 Stable at pH range 4-11
`0 Odorless, tasteless
`
`Spmy dfild a1Irlcol‘RC-591
`
`Emil
`
`2
`
`000003
`
`000003
`
`

`

`Avice|® RC-591
`
`- A water dispersible organic hydrocolloid used in
`the preparation of pharmaceutical suspensions
`and emulsions.
`
`The colloidal MCC provides a structured dispersion
`vehicle while the CIVIC facilitates dispersion and
`serves as a protective colloid.
`
`- A spray-dried blend of microcrystalline cellulose
`(E103 and sodium carboxymethylcellulose
`
`( M .
`
`Avlcol Colfoidnl MCC
`{lnsoluhk cnmpanunu
`
`
`
`
`Sodivm carboxynnlhylcuuulon
`(Soluble component)
`
`Ital‘
`
`Powder particle of
`Avlcfl RC-59!‘
`
`parade shows lightly
`Cu!
`pm: ad mlcmcmsms
`
` 3
`
`000004
`
`000004
`
`

`

`Structure and Function
`
`Microcrystals of Avicel microcrystalline cellulose
`are leashed together with chains of soluble CMC
`to form a mesh-like powder particle (Fig.1).
`
`Figure l.—Powderp|r1lcle Arise! RC-ml
`
`Due to the small size of the microcrystals (approxi-
`mately 60% of the crystallites in dispersion are
`<02 ulvl), there are a arge number of microcrystals
`packed in each powder particle. (Fig. 2).
`
`The large number of small. microcrystal particles
`help promote
`
`0 Slower more uniform settling rate
`
`- Suspension stability
`
`0 Formulation elegance
`
`0 Absence of hard packing
`
`The highly compact nature of the powder particle Is
`evident in this scanning eiectromicrograph (Fig. 3).
`
`
`
`powder particle 30 pM In
`eier typicalty contains
`million 0.1 pM Avicel RC
`rocrystals.
`1plV| particte contains about
`000 0 1 pM microcrystals
`
`
`
`Filguru 3. Cut powdbr parflclo
`
`4
`
`000005
`
`000005
`
`

`

`Structure and Function (continued)
`
`In the presence of water and mild shear, the
`Avicel' RC-591 powder particles swell and are
`then peptized. forming a dispersion of cellulose
`microcrystals. These microcrystals create a
`stable lattice structure for use in the formulation
`of suspensions and emulsions. (Fig. 4).
`
`0 Concentrations <1% solids form colloid
`
`dispersions.
`
`- Concentrations >1% solids form thixotropic
`
`.
`
`'
`
`I
`
`_
`
`u
`_
`
`.-
`.-
`
`v
`
`.
`
`_
`
`I
`
`_
`
`-
`
`-
`
`4
`.
`
`-
`
`.
`
`“
`
`_
`
`:
`
`.
`
`.
`
`.
`IE" .
`‘I
`
`,
`"
`I
`
`,9‘
`._r
`
`I
`
`-.
`
`.
`1
`‘I "in
`I
`
`_
`
`_.
`
`_
`
`.
`
`gels.
`
`-
`
`I
`
`__
`
`l'_
`
`_
`
`.-
`
`‘-
`
`--
`
`‘I
`
`_.-.
`
`.
`i
`'
`_ '
`'
`__
`.
`.I_I
`.
`.
`-
`"
`r H
`. -'
`2.-
`.
`.
`.-.-
`.
`' ""'Ir
`-‘L. ‘I
`I''‘- r":;"'.'£-'lis-"r
`mu 4. —Fully popllznd factlulndl Avicol coaoidu niicmcrnuliru urrulou
`
`Rheological Properties
`
`Thixotropy
`
`Avicel RC-591 gels are highly thixotropic and have
`a finite yield value which begins approximately at
`a 1% solids concentration. (Fig. 5).
`
`245
`
`130
`
`'
`
`I
`.
`
`:5"
`E
`
`I 2
`"' 120
`
`60
`
`O
`
`.
`
`O
`
`T
`
`‘
`
`-
`I
`lI
`
`1
`
`0.5
`
`1.0
`
`20
`%cor'centratlon
`
`3.0
`
`Figaro 5.—Yi¢ld unniu. 1.-n:cun_lr_u'Iion nf R-C-591. l’-5'6
`
`5
`
`000006
`
`000006
`
`

`

`Process
`
`The thixotropy and yield value of FlC-591 gels are
`due to the lattice structure formed by the micro-
`crystals. When a shearing force is applied to the
`gel, the particles separate and align with a corre-
`sponding reduction in resistance to flow (shear
`thinning). Then. as the dispersion is allowed to
`rest, a yield value is re-established and the solid
`particles refonn the mesh-like network (Fig. 5).
`
`Effects of Hydrocolloids
`Figure 7 illustrates how the thixotropic nature of
`Avicel’ RC-591 decreases with the addition of
`CMC. This same phenomenon occurs with mix-
`tures of RC-591 and methyl cellulose. RC-591 has
`a synergistic effect on the viscosity of Keltrol“,
`magnesium aluminum silicate, and various other
`gums.
`
`Effect of Temperature
`Changes in temperature have little effect on the
`viscosity of Avicel RC-591 dispersions. This is
`beneficial in maintaining long-term stability (Fig. 8).
`
`Effect of pH
`wscosity is stable over a pH range from 4.0-11.0.
`
`\.
`
`.6\/\/—> é ——-bl
`/I /\
`C:-;_—/,-:23
`Rest
`Mlcr:ta|s
`“Shear
`attest
`
`'\
`
`I
`
`010203040506DTOB090
`seem HATE-sec-1
`
`i___.- .,
`ofnn Avlcdflc dfsporsfnn and.
`ngm z—nau}
`$9 blend‘ of Avian! RCICMC-TMF
`
`
`
`
`DISPEHSIONS
`
`reU1
`
`.9‘:
`
`CHANGEINVISC
`
`75
`
`100
`25 30
`
`60
`50
`TEMPERATURE. " C
`F-lgun &—EtIaeto—framporiIuru on viscosity
`
`40
`
`T0
`
`6
`
`000007
`
`000007
`
`

`

`RC-591 as a Suspending Agent
`
`Avicel” RC-591 microcrystalline cellulose, either
`alone or in combination with other hydrocolloids,
`is an excellent suspending agent. Formulations
`containing 1.2% RC-591 are well structured sus-
`pension vehicles, thixotropic. and have a finite
`yield value.
`
`Suspended materials are either
`
`- Allowed to settle and can be redispersed. or
`
`- Kept in suspension with very little phase
`separation.
`
`
`
`3*: I-
`.-
`.
`.
`Flguru I‘l.—undl‘spIrud syslrm
`
`Flocculating/Electrolytes
`Dispersions of Avicel RC-591 are readily flocculated
`by small amounts of electrolytes, cationic polymers,
`and surfactants. This flocculated colloidal dis-
`persion settles but prevents hard packing of sus-
`pended materials.
`
`Protective Colloids
`
`Because Avicel RC-591 colloidal dispersions
`contain a high concentration of particles smaller
`than 0.2 uM and have a finite yield value. a stable,
`elegant suspension may be formulated.
`
`When RC-591 is used with protective colloids.
`the mixed system combines the stability of the
`polymer solution with the yield value and disper-
`sion of the microcrystals to form a long lasting
`suspension.
`
`The best protective colloids for use in RC-591
`dispersions are:
`
`- Xanthan gum
`
`- CMC lcaiboxymethylcellulosel
`- Methoce|" 90 HG
`hydroxypropylmethylcellulose
`
`7
`
`000008
`
`000008
`
`

`

`
`
`96orAvicelRC-591Dispersed(Peptizedj S3!
`
`D33
`
`Egan Avlcel FlC-591
`parts dlstrlled water
`
`1.5%
`dispersion
`
`Figaro l1—$unoatod ifiaporalun ratio
`
`100%
`
`
`
`
`
`
`
`30160 240 320 400480 560640
`PPM Monovalentsalis
`
`Dispersion Factors
`
`When stirred in water, Avicel-" FlC—591 powder
`disperses to form either a colloidal sol or white
`opaque gel. depending upon the Avicel RC
`concentration.
`
`Water Addition
`
`Avicel RG~591 can be added to water very easily.
`Two important things should be noted:
`
`- Sufficient water should be available for easy
`dispersion.
`
`- FIG-591 should be dispersed in water prior to
`the addition of other formulation ingredients.
`The few exceptions are seen with preservatives
`such as methyl and/or propylparaben. and
`sodium benzoate. (Fig. 12).
`
`Preparation
`To prepare a product containing a 1.5% concen-
`tration of Avicel RC-591. the dispersion ratio
`shown in Fig. 13 is recommended.
`
`This ratio results in a lump—free dispersion which
`can be easily handled in processing.
`
`The functionality of Avicel RC-591 may be
`severely affected when other ingredients are
`added to water first. Neither a thixotropic system
`nor a structured vehicle may be obtained.
`
`Equipment
`Standard laboratory and production equipment
`can be used to prepare dispersions of Avicel
`RC-591 MCC in monovalent salt solutions. Fig. 14
`illustrates that a high~speed propeller mixer will
`provide adequate shear for proper dispersion at the
`most common concentration levels of these salts.
`
`A. Propeller Mlxer— B. Priggeller Mixer- C.Centrifugal D.Warlng
`Low Speed
`H
`Pump
`Blender’
`Flynn 1-I. Equ-‘prnlnl type: nquind for nrioul PPM manoulont um
`
`000009
`
`000009
`
`

`

`Dispersion Factors (continued)
`
`Temperature
`Avicel” RC-591 microcrystalline cellulose can
`be dispersed in either hot or cold water. A lower
`viscosity is obtained when hot water (>60°C) is
`used. Thixotropy is also reduced but remains a
`characteristic flow property.
`
`Glycols/Polyols
`Avicel RC-591 will not disperse in glycols or alco-
`hols alone. However. once an aqueous dispersion
`
`is formed, water miscible liquids can be added
`
`Fig. 15).
`
`A formulation requiring a large quantity of glycols
`may have a limited amount of water available for
`an RC—591 dispersion. In this case, a portion of
`the water may be replaced with glycerin or sorbitol
`70%. Figure 16 shows examples of ‘‘replacement'‘
`quantities and the resulting viscosities. However,
`substituting even a portion of the water used to
`disperse Avicel RC-591 is not recommended.
`(Fig. 16).
`
`If hot water must be used in dispersing RC-591
`when a high viscosity is also required, then
`approximately 0.5% additional Avicel RC—591 will
`compensate for the temperature difference.
`
`Compatibility of Avicel HG-591 with Misclble Liquids
`
`Parts of 1% Avicel RC-591 DispersionlParts of
`Water Mlsclble Liquid:
`40160 Ethanol
`40160 Propylene Glycol
`.
`40/60 Glycerine
`40160 Sorbitol Solution (70%)
`|
`IL._ T . .. _ ..-...-.—.-
`
`Viscosity comparisons of 3.75% Avic—eI RC-591
`
`Dispersions With GlycolsIPolyols
`
`000010
`
`000010
`
`

`

`Avice|® RC-591 Microscopic Features
`
`Avian!‘ RC-$1 all Ind‘ watur emulsion
`
`Fuflr disparnd Avian‘ RC uxponxhn
`
`000011
`
`000011
`
`

`

`Avicel® RC-591 as an Emulsion Stabilizer
`
`Avicel RC-591 particles make excellent emulsifying
`agents or emulsion stabilizers for oil-in-water
`systems. This is due to the unique crystalline
`structure of cellulose from which RC-591 is
`
`derived. (Fig. 17).
`
`Avicel RC-591 colloidal particles help create a
`stable oil-in-water emulsion by:
`- Congregating at the ollfwater interface
`
`o Fleducing oil droplet movement and possible
`coalescence when suffioient FlC-591 is used to
`produce a yield value in the aqueous phase
`
`Mechanism
`
`Avicel particles are wetted by oil and water. The
`particles reside at the oil/water interface producing
`an interfacial film of considerable strength and
`stability. (Fig. 18).
`
`The film formation is a result of the molecular
`character of cellulose as well as the Avicel FiC-591
`crystalline structure. It has been observed that
`hydroxyl groups available within the lattice of the
`cellulose molecules are aligned in one plane. The
`two hydroxyl dominant sides of the crystal have
`an affinity for water while the remaining two sides
`of the crystal are more readily wetted by oil.
`Therefore, the crystals line up at the oil/water
`interface to physically structure an emulsion.
`
`F9 15 MCC stab ze emu SIOFIS
`
`‘H
`
`000012
`
`000012
`
`

`

`Manufacturing
`0 Because Avicel‘° RC-591 microcrystalline cellu-
`lose does not lower the interfacial tension of an
`oil/water system, high shear must be used to
`produce small oil droplets.
`
`- Avicel RC-591 must be dispersed in water prior
`to the addition of other water soluble excipients.
`(Do not add RC-591 powder directly to the
`emulsion after the oil and water phases have
`been combined.)
`
`0 Small amounts of surface active materials
`should be added to a formulation to produce
`an emulsion of very small particle size.
`
`Stability
`Emulsions made with Avicel RC-591 are stable:
`
`0 Under sterilization conditions
`
`0 After prolonged storage
`
`0 Under freeze—thaw and stress testing conditions
`
`Undfsperud Mica! RC-591 umursion nysrom
`
`000013
`
`000013
`
`

`

`Avicel® Colloidal Dispersion Procedures
`
`Avicel colloidal (RC/CL grades) microcrystalline
`cellulose products are water-dispersible, water-
`insoluble hydrocolloid materials used in the
`preparation of pharmaceutical suspensions and
`emulsions. These products are co-processed
`mixtures of microcrystalline cellulose (MCC) and
`sodium carboxymethylcellulose (CMC). The MCC
`provides a stmctured dispersion vehicle while the
`CIVIC serves as a protective colloid, as well as
`facilitating dispersion. This section describes tech-
`niques and critical factors in dispersing Avicel
`colloidal and demonstrates performance attributes
`due to proper and improper dispersion.
`
`When fully dispersed in water, these products
`possess unique functionality as structured. thixo-
`tropic gel systems. Proper dispersion of Avicel
`colloidal is critical to obtaining this functionality.
`If the Avicel is flocculated or not completely dis-
`persed, the performance of the formulation will
`not be at its optimum level; inconsistent viscosity
`and performance results will be obtained.
`
`Key factors to consider when
`dispersing Avicel RC/CL
`products are:
`Order of addition -- Avicel colloidal should be
`dispersed in water before other ingredients are
`added. Avicel does not bind water like other
`hydrocolloids and. therefore, will not interfere with
`the subsequent addition of other ingredients.
`However, water availability is important in the
`dispersion step to aid distribution of shearing
`energy to insure full dispersion.
`
`Type of shear —T11e Avicel colloidal product used
`depends upon the amount of shear available in
`your process.The most readily dispersible prod-
`ucts, Avicel“ FlC-591 and CL-611, can be fully
`dispersed with high speed mixing (e.g. Silverson",
`Cherry—Burrell’). Less easily dispersed is Avicel
`FiC—581, which requires homogenization (Fig. 19,
`Page 14). Homogenization of FlC-591 and CL-611
`dispersions can affect ultimate gel strength (Fig. 20,
`Page 15).
`
`How to verify dispersion
`- \frsible clumps of powder are clearly indicative
`of undispersed material. Beyond that, however.
`the verification of proper dispersion requires an
`analytical approach.
`
`- The most certain measure is to match your
`dispersion characteristics to a proper disper-
`sion curve profile. Chart 1 demonstrates the
`dispersion profile of a typical FIG-591 product.
`Initially, viscosity increases dramatically. This
`is a common effect when dispersing/dissolving
`gums and is caused by the apparent viscosity
`of undispersed lumps of material. As shear
`continues. the viscosity begins to drop and
`eventually becomes less apparent; it is at this
`point that Avicel can be said to be properly
`dispersed.
`
`- This approach should be used in both product
`development and scaleup to verify dispersion.
`
`o An optical method is a less precise. but some-
`times adequate, means of checking dispersion.
`The photographs under polarized light show
`fully dispersed and undispersed Avicel.
`
`
`
`Two minutes in
`Waring Blender‘
`
`VISCOSITY
`
`O
`
`SHEAR
`
`55:: r Jorspsnsiou moms. Show vs |fi.|_¢:ash‘y_ '
`
`13
`000014
`
`000014
`
`

`

`Checking Your Dispersion
`0 If Avicel’ microcrystalline cellulose did not achieve
`dispersion. clumps of powder will be visible.
`
`- if Avicel is properly dispersed, you will see a very
`even crystalline pattern under polarized light.
`
`- If your dispersion is flocculated, you will see
`gaps where no rnicrocrystals are present.
`
`- To prevent flocculation, we recommend that a
`protective colloid be added immediately after
`dispersing Avicel. Carboxymethylcellulose and
`xanthan gum are the best protective colloids and
`should be added at 15-20% of the weight of
`Avicel. These colloids can also beneficially affect
`suspension properties.
`
`
`
`
` max patarimr ugm
`
`Factors that can interfere with
`obtaining a good dispersion
`- Inadequate shear —- refer to dispersion
`methods.
`
`- Hard waterlelectrolytes —— cations can cause
`flocculation.
`
`I Improper order of addition ——- as noted above.
`Avicel‘ should be dispersed before addition of
`other ingredients.
`
`- To prevent flocculation, protective colloids such
`as xanthan, methylcellulose, and carboxymethyl—
`cellulose can be added, generally at 15-20%
`wlw % of Avicel.
`
`- Low pH - if the pH of the system is less than 4,
`a protective colloid may be needed.
`
`Examples
`While each mixing/dispersion system may be
`different, the following examples illustrate the
`requirements and relative dispersion performance
`of various dispersion mechanisms with varying
`batch sizes. Your own system should be evaluated
`to insure the proper dispersion times for the type
`of equipment and batch size. The following l-“Igures
`(19. 20, 21) describe: Dispersion of Avicel RC-591;
`Comparison of Avicel FiC~591 to Other Avicel
`Colloidal Types; and Effect of Concentration of
`Avicel RC-591.
`
`Dispersion Equipment
`
`Silverson' L 2 Fl
`Silverson L 2 Ft
`Pressindustria TE3 VR 10
`Pressindustria TE3 VR 50
`Silverson BX
`Silverson BX
`Silverson GX 1D or FX 10
`
`Batch size
`_
`
`perslon time
`
`(Merl
`
`Pressindustria BEMSX type 55
`Figure I9. -Dispersion of Avicel RC-591
`
`NO TE: Ezamplos anphr to maximum 2% concentration.
`
`14
`
`000015
`
`000015
`
`

`

`Comparing three types of Avice1" microcrystalline cellulose and the influence of concentration
`and homogenization. Batch size was 1 liter. Avlcel was dispersed in demlneralized water by
`stirring with a propeller at 500 rpm during 30 minutes.
`
`Concentration
`mg/ml
`12
`12
`12
`12
`20
`20
`20
`25
`25
`12
`12
`14
`14
`16
`16
`
`Homogenizetion
`time. minutes
`
`or-o3—=—Ac3—-cam-o--o-0
`
`Yield value
`Pa
`4.8
`8.7
`0.6
`0.25
`7.0
`5.6
`2.5
`12.9
`11.9
`0
`4.3
`4.5
`5.0
`6.3
`7.9
`
`oz;-_:-7r_<_*':cc)"nn'lOOCD
`
`Conclusion:
`
`Avicel RC-581 has to be homogenized.
`Avicel FiC-591 has a much higher yietd value when it is homogenized.
`Avicel CL-611 has the highest yield value when it is not homogenized.
`Comparable results: FIC-591 at 12 mg/ml homogenized. FtC—581 at 16 rng/ml
`homogenized, and CL-611 at 22 mg/ml not homogenized.
`Figure 20. --Cornpulaorr or Avicol R6455! to other Avical colioldaf typos
`
`Concentration. mg/ml
`
`\fIscosity at 201 s~1, mPas
`
`
`
`Conclusion: 12-14 mg/ml is the right concentration for suspensions.
`Figaro 2!.--Effect of coucunlmlion of Aricel RC-59!‘
`
`15
`
`000016
`
`000016
`
`

`

`Wscosity Measurement as Measure
`of Dispersion
`One of the measures used to evaluate hydrocol-
`Ioid dispersions is the measure of viscosity.
`Avicel‘ RC/CL products are thixotropic. A valuable
`property of thixotropic dispersions is that they
`establish a gel with a measurable yield point.
`Upon shear above the yield point the gels break
`to form a readily pourable liquid. The gel immedi-
`ately begins to reform when shear is removed.
`Depending on the formulation, concentration of
`
`Methods of Dispersion
`
`Avicel, etc., the time to full gel reformation may
`vary. The viscosity measurement of gel-forming
`materials is very dependent on reproducibility in
`carrying out the analytical method. When compar-
`ing results to data obtained by other groups, it
`is very important to insure that methods, instru-
`ments, instrument settings and procedures are
`carried out exactly.
`
`The steps necessary to properly disperse each
`grade of Avicel are described below.
`
`Avlcel
`
`Bulk—Dried Avicel Colloidal
`
`This procedure pertains to Avicel FlC-581 which
`requires homogenization for dispersion.
`
`Procedure
`
`- Add Avicel to water while agitating.
`
`- Add protective colloids (if required).
`
`- Agitate 10-15 minutes.
`
`- Add other ingredients.
`
`- Hold the salt and acids until last.
`
`0 Homogenize at 2000 psi.
`
`Batch tank
`
`§
`
`Hornogenlznr
`
`'7
`
`'18
`000017
`
`000017
`
`

`

`Methods of Dispersion (continued)
`
`Spray_Dried Avicelfl Co||0ida|
`This Procedure pertains to Avicel microcrystalline
`cellulose types RC—591 and CL—t-311 which require
`rapid agitation in water for dispersion.
`
`Option lll: High-speed blending tank
`' Using °"'t31’”Ae.Wfite';(§§"fi°'g°f“?.e.bat°'?.- T
`3°t""atet 9 ‘"5"’ F’
`“Ct V U“ ‘z'"‘3 3 'q”' '9'
`type di5pe’3i°" tam‘-
`- Mix for 3 minutes.
`
`__
`
`_
`
`,3a,.,., .5...‘
`
`PTOC‘-edUl'e
`_
`'
`_
`Option I: High-speed mixer
`
`- Add Avicei to the water while agitating.
`
`- Follow with a protective colloid if the pH of your
`system is less than 4.
`
`_ "H E In
`
`Hlghlspaad
`blending tank
`Mic...
`
`1
`
`- Agitate with high velocity agitator for
`10-15 minutes.
`
`- Add the other ingredients.
`- Hold the salt and acids until last.
`
`Avlcal
`
`Batch tank
`with high
`speed mixer
`
`._ _j_ _
`
`.._ T an
`
`Option ll: Funnel with blender pump
`
`- Using only the water portion of the batch.
`activate Avicel using an ingredient funnel with
`a pump.
`
`- Continue pumping for 10-15 minutes following
`the addition of Avicel.
`
`Avlcel
`
`li
`
`Funnel with
`blender pump
`
`
`
`000018
`
`

`

`Summarizing...
`
`Avicel® RC-591 microcrystalline
`cellulose is a versatile, colloidal
`dispersion vehicle with broad
`pharmaceutical applications:
`- Suspending agent
`- Emulsion stabilizer
`
`0 Oil/water emulsifier
`
`Formulation Benefits of Avicel RC-591
`
`- Modifies viscosity
`4- Possesses thixotropic
`properties
`Ir Stable under extreme
`temperatures
`
`- Stable over wide pH
`range
`- Long shelf-life stability
`
`18
`
`000019
`
`000019
`
`

`

`FMC Corporation
`FMC BioPolymer
`United States
`Philadelphia, Pennsylvania
`
`Europe
`Brussels. Belgium
`
`Asia-Pacific
`Hong Kong
`
`Latin America
`Montevideo. Uruguay
`
`Middle East
`Amman, Jordan
`
`Sales/Technical Assistance:
`Tel:
`1 215 299 6534
`Fax: 1 215 299 6669
`
`Sales/'I’echnlcal Assistance:
`Tel: +32 2 775 8311
`Fax: +32 2 775 3300
`
`Tel‘. +852 2839 6600
`Fax’. +352 2576 3770
`
`Tel!Fax: +5982 6043030
`Tel/Fax: +5982 6043104
`
`Tel: +962 6 4618150
`Fax: +962 6 4613156
`
`Customer Service:
`Tel:
`1 800 526 3549
`Fax‘. 1 215 299 6475
`
`Customer Service:
`Tel: +353 21 4354 133
`Fax: +353 21 4353 057
`
`Tokyo. Japan
`
`Tel: +51 3 3402 3739
`Fax; +81 3 3402 3700
`
`www.fmcbiopoIymer.com
`pharm_info@fmc.com
`
`Patents
`
`FMC Commotion does not wan-ant against lntringement of patents oi third fla|1!95 by
`reason of any uses made of the product in combination with other material or in the
`operation oi any process, and purchasers assume all risks of patent i.-rim-gement by
`reason oi any such use. combination or operation.
`
`The products. processes and uses thereoi described herein are covered by one or
`more patent applications or patents.
`
`Warranty
`
`Because of the numerous factors aliecting results FMC ingredients are sod on the
`understanding that parchrtsers will make their own test to determine the suitability of
`these products for their particular purpose The several uses suggested by FMC
`Corporation are presented only to assist our customers In exploring possible applica-
`tions. All lnlorrnation and data presented are believed to be accurate and reliable. but
`are presented without the assumption of any liability by FMC Corporation.
`
`Technical Service
`
`In nature.
`The information contained In this bulletin is intended to be general
`Techniques and data pertaining to speciiic uses tor FMC ingredients and new
`developments will be published periodically in the form oi supple-nental application
`bulletins.
`
`Our technical stafi is ready to offer assistance in the use of Avicel’ RC-591.
`
`Regulatory Status
`
`Avicel RC-591. a colloid iorming attrlted mixture of microcrystalline cellulose and
`carboxymethylcellulose sodium. meet the standards set forth in the United States
`Phannacopoeiamational Forrnutary tor "microcrystaIline ce lulose and carboxymelhy|-
`cellulose sodium" and in the British Pharmacopoeia for d spersible cellulose.
`
`The colloid forming attrited mixtures of mlcrocrystaillne cellulose and sodium
`carboxyrnethylcellulose are generally recognized as sale (GRAS) by qualified experts.
`FMC maintains a Type IV Drug Master File (Exciplents) to support the use oi Avicel
`FlC-591 in drug products.
`
`FMC. Avlcel, Not Just Products. Partners. - FMC Trademarks.
`Silverson - Silverson Machines Ltd. Trademark.
`Methocel - The Dow Chemical Co. Trademark.
`Waring and Blender - Dynamics Corp. of America Trademark.
`Cherry-Burrell - Cherry-Burrell Corp. Trademark.
`
`©1994 FMC Corporation. All rights reserved.
`
`FIC-591 (5199)
`
`000020
`
`000020
`
`