6 •3
`
`The table on page 6• 4 provides further information
`regarding correlation of number average molecular
`weight with the commercial viscosity designation. To
`interpret or to extend the table, plot the first column as
`abscissa and the others as ordinates on bi-logarithmic
`paper.
`The date in the right-hand column represents the Num(cid:173)
`ber of Average Molecular Weight for METHOCEL A
`cellulose ether and was obtained from osmotic pres(cid:173)
`sures. The Number Average OPn was obtained by divid(cid:173)
`ing Mn by the unit molecular weight of186. To obtain the
`Number Average Molecular Weights for the other
`METHOCEL cellulose ether products, the following Unit
`MolecularWeights must be used: METHOCEL "E", 201;
`METHOCEL "F", 195; METHOCEL "J", 222; METHOCEL
`"K", 192; and METHOCEL "HB", 195.
`Intrinsic Viscosity is the I imiting quotient of the speciffic
`viscosity divided by the concentration as infinite dilution
`is approached (that is, as the concentration approaches
`zero). The Number Average Molecular Weight is calcu(cid:173)
`lated from the limiting osmotic pressure of the solvent
`as the concentration of the solute approaches zero. The
`weight average molecular weight will be 3-10 times the
`Mn depending on the viscosity grade. Lower viscosity
`products require multiplying factors that are larger.
`
`-Continued
`
`SOLUTION
`
`VISCOSITY
`Molecular Weight-Viscosity
`Relationship
`METHOCEL cellulose ether products are linear poylmers
`consisting of anhydroglucose rings to which various
`substituent groups have been attached. The apparent
`viscosity is proportional to molecular weight or chain
`length of the METHOCEL cellulose ether products.
`Commercial designations of METHOCEL cellulose ether
`products are based on viscosity values determined in
`water at 20"C and at a concentration of two percent
`cellulose derivative content. The methods are described
`in ASTM monographs 01347-72 and 02363-72.
`
`Molecular Weight I Viscosity Correlation 200C
`
`100,000
`
`I
`I
`
`I
`
`I! I
`1
`
`11
`
`I
`
`I
`
`10,000
`
`1000
`
`100
`
`f-+-
`
`10
`
`'
`I
`I I
`I I
`
`I
`
`I
`
`I
`/~ I
`
`I
`
`I
`
`I
`
`!
`
`'
`
`I
`
`I
`
`I I
`
`I
`
`'
`
`I
`l.t Mw
`-
`
`'
`
`I
`1/1
`I I
`
`l
`
`;I
`
`I
`I
`
`10,000
`100,000
`1000
`NUMBER& WEIGHT AVERAGEMDLECULARWEIGHT - M,, M.
`
`@ 1974, 1978, The Dow Chemical Company
`
`NOTICE- This information is presented in good faith, but no warranty, express or implied, is given nor is freedom from any patent
`owned by The Dow Chemical Company or by others to be inferred. Inasmuch as any assistance furnished by Dow with reference
`to the proper use and disposal of its products is provided without charge, Dow assumes no obligation or liability therefor.
`
`THE DOW CHEMICAL COMPANY • DESIGNED PRODUCTS DEPARTMENT • MIDLAND MICHIGAN 48640
`
`Printed in U.S.A.
`
`~
`
`• Tr::ati~m::arlt nf Tha nnw r.ht:amir~l r.nmn::anv
`
`Form No. 192-684-78
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 45/86
`
`

`

`6 • 4
`
`SOLUTION
`
`Viscosities of Methylcellulose of Various Molecular Weights
`.
`.
`
`Viscosity Grade
`2%, 20"C, cP
`
`Intrinsic Viscosity
`(n), dl/ g at 21J"C
`
`'
`
`Number Average
`. DP.
`
`<
`
`Number Average Molecular
`Weight, M.
`
`I
`
`10,000
`1.2
`5
`53
`13,000
`70
`1.4
`10
`20,000
`110
`2.05
`40
`26,000
`2.65
`100
`140
`41,000
`400
`220
`3.90
`63,000
`1,500
`340
`5.7
`86,000
`4,000
`460
`7.5
`110,000
`8,000
`580
`9.3
`120,000
`15,000
`650
`11.0
`140,000
`19,000
`750
`12.0
`180,000
`40,000
`950
`15.0
`220,000
`1,160
`75,000
`18.4
`From Encyclopaedia of Polymer Science and Technology, 3, p. 504. lnterscience, John Wiley & Sons, N.Y. and
`London, 1965.
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 46/86
`
`

`

`Effect of Concentration on Viscosity
`
`An application or end product formulation usually re(cid:173)
`quires a predetermined METHOCEL cellulose ether
`product viscosity. The following charts provide the con(cid:173)
`centrations ofthe various viscosity METHOCEL cellulose
`ether products that will produce the desired viscosity.
`
`They illustrate the viscosity-concentration relationships
`for METHOCEL cellulose ether products at 20°C (68°F).
`The data in the graphs represent the average material
`found within a viscosity specification. The shaded areas
`indicate the range of viscosity that may be obtained for a
`given METHOCEL cellulose ether products.
`
`METHOCEL cellulose ether products. These graphs are
`prepared on 8th root, not on logarithmic paper. The 8th
`root of the viscosity is a roughly linear function of the
`concentration. To chart the line for any intermediate
`grade, locate the desired 2 percent viscosity above 2
`percent on the abscissa and draw a straight line to the
`point of origin.
`
`Blends of the METHOCEL E products also can be used to
`obtain a range of required viscosity and film properties.
`Examples of viscosity response with different blends of
`polymer at concentration of 5 and 10%, and related
`blending curves, are shown in the Figures under "Rec(cid:173)
`ommended Concentrations," page 6•13.
`
`The figures depict the viscosity-concentration relation(cid:173)
`ships for solutions of low- and high-molecular-weight
`
`The data shown were measured in water as "solvent", at
`20°C, using an U bbelohde viscometer (ASTM 02363-72).
`
`Viscosity-Concentration Chart for
`High- Viscosity METHOCEL
`
`Viscosity-Concentration Chart for Low Viscosity
`METHOCEL Products
`
`1011.000
`
`70,0011
`50,0110
`40,000
`30,000
`
`20,0110
`15,000
`
`If /),
`p~++n In
`I ~
`II?
`rh
`~~00 -II fJ
`VII A
`L
`15,000 {1-i J-.IJ
`VII
`r/
`'" w
`r /JI//
`'/. v
`// VI
`1/U /J
`h
`Ill/
`'.f.
`rA A
`I, ~
`I.
`,.,
`/U
`lW
`
`1--- 4~00
`
`f i .
`
`""" ~
`~
`L r7
`~ v
`
`/:
`
`-~
`1,500
`
`10,0011
`7,000
`u
`5,0110
`~ 4.000
`@)
`3,0110
`2,0110
`1.5011
`1,000
`700
`SOD
`4011
`3110
`~!!8
`1011
`70
`50
`40
`25
`15
`10
`5
`3
`2
`1 D
`
`50,0011
`40,0110
`30,000
`
`20,000
`15,0110
`
`10,0011
`7.000
`5,0011
`4,0011
`3.000
`2,0011
`1,5011
`1,0011
`7011
`SOD
`400
`300
`200
`100
`70
`40
`25
`10
`5
`3
`2
`1
`
`u
`~
`@)
`a..
`u
`ll
`
`"' Cl u :;
`
`-
`:- r-
`i -
`
`~-
`
`t--
`
`50
`
`r-r.t.
`Fl.
`I "
`"
`U /
`" I
`
`- F= 1-
`
`f-
`I-
`i -
`
`~J
`
`.u r
`rn
`I "'
`!1. / A ~ .....
`~ ~
`
`-D
`
`,I
`
`I
`
`-r r
`)$- 15
`w
`"'"
`, ./'.V
`, ......
`
`r?-~
`l7, _,
`~
`/'~
`
`5
`
`1:=
`f -
`f -
`r=
`
`10
`
`12
`
`14
`
`f -
`
`I.
`
`m
`MII/I • "
`Ill// II
`ru
`' I
`•
`'-"
`
`I J
`11/.
`
`~ r,
`
`400
`
`~
`'U
`
`'
`
`IW
`
`II
`
`~ - 100
`
`I
`
`3
`% METHOCEL Cellulose Ether
`
`Concentration, % of METHOCEL
`
`© 1978, The Dow Chemical Company
`
`NOTICE- This information is presented in good faith, but no warranty, express or implied, is given nor is freedom from any patent
`owned by The Dow Chemical Company or by others to be inferred. Inasmuch as any assistance furnished by Dow with reference
`to the proper use and disposal of its products is provided without charge, Dow assumes no obligation or liability therefor.
`
`THE DOW CHEMICAL COMPANY • DESIGNED PRODUCTS DEPARTMENT • MIDLAND MICHIGAN 48640
`
`Printed in U.S.A.
`
`~
`
`• Tr~r4.o.rnorL, nf Tho nn'a' t"horni,..ol r.:nrnn!:llnu
`
`Form No. 192-685-78
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 47/86
`
`

`

`6 •6
`
`SOLUTION
`Blending for Intermediate Viscosity
`METHOCEL cellulose ether products of the same sub(cid:173)
`stitution type but of different viscosity grades can be
`blended to obtain an intermediate viscosity grade. The
`figure following is a blending chart that can be used
`for this purpose. The points corresponding to the
`viscosities of the two starting materials are selected
`on the two vertical scales and connected with a line.
`The point corresponding to the desired final viscosity
`
`is then located on one of the vertical scales and a
`horizontal line drawn from it to the first line. The
`percent of right-hand-scale material needed to make
`up the blend can then be read from the bottom scale.
`The example on the chart shows that 60 percent of
`15,000 cps material and 40 percent of 400 cps
`material are needed to make a blend having a viscosity
`of 4,000 cps. Similarly, 50 percent of 25 cps material
`and 50 percent of 1 00 cps material yield a blend with a
`viscosity of 50 cps.
`
`Blending Chart for METHOCEL Cellulose Ether Products
`
`100,000
`
`75,000
`
`50,000
`
`15,000
`
`10,000
`
`4,000
`
`1,500
`
`1.000
`
`400
`250
`
`100
`
`50
`
`25
`15
`
`10
`
`C,)
`
`~
`tA
`1:1.
`C,)
`~-
`Vi
`Q
`C,)
`Cl.l >
`
`~ II"""
`
`/
`
`400
`
`/ ....--
`~---- -· ~-
`---I
`
`•
`
`15,000 y
`v ~
`
`v
`
`.....
`
`,,
`
`4,000
`
`...
`
`./v v
`
`50
`
`II_
`
`--
`
`100-
`
`i t - -- -
`
`~
`
`2% Cone. in water
`
`0
`
`20
`
`60
`40
`% of Right-Hand Material
`
`80
`
`100
`
`-Continued
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 48/86
`
`

`

`SOLUTION
`Effect of pH on Viscosity
`Because METHOCEL methylcellulose and METHOCEL
`hydroxypropyl methylcellulose are nonionic, the vis(cid:173)
`cosities of their solutions are generally stable over a
`wider pH range than are the viscosities of those gums
`which are ionic in nature. Outside the range of pH 3 to 11,
`however, there may be a gradual loss of viscosity at
`higher temperatures or after longer periods of standing,
`especially with high viscosity solutions. Solutions of
`METHOCEL cellulose ether products in strong acids or in
`strong caustic solutions will decrease in viscosity. This
`factor should be considered when determining the shelf
`life of products.
`
`Effect of Additives on Viscosity
`In the preparation of formulations, viscosities may occa(cid:173)
`sionally be considerably higher than expected. This
`phenomenon can be caused by interaction of the
`METHOCEL cellulose ether product with one or more of
`the formula ingredients. As a result, it may be possible to
`use less thickener and still have adequate thickening.
`This effect usually passes through a maximum which is
`dependent on the concentration of the interacting mate(cid:173)
`rials and on the presence of other ingredients such as
`pigments, latex particles, or preservatives. In sys(cid:173)
`tems having lower concentrations of additives, - 1%,
`METHOCEL A or METHOCEL K products may be suit(cid:173)
`able. However, in systems where the concentration of
`additives are rather high, -10%, the more highly sub(cid:173)
`stituted products such as METHOCEL E or METHOCEL J
`
`© 1974, 1979, The Dow Chemical Company
`
`may be more compatible due to their increased organic
`compatibility. The effect will also vary with the purity of
`the specific reagent and with the manufacturing source.
`Effects of various additives on the viscosity of 1%
`solutions of METHOCEL is seen in the table on page 6• 8.
`
`Revised 2/79
`6 • 7
`
`If a manufacturer wishes to minimize the increase
`in viscosity obtained from certain additives, the
`METHOCEL cellulose ether product or the additive
`should be blended separately into the formulation, pref(cid:173)
`erably at a point where dilution of one of these ingre(cid:173)
`dients takes place. It should be noted that certain
`surfactants at high concentration will precipitate
`METHOCEL cellulose ether product.
`
`-Continued
`
`NOTICE- This information is presented In good faith, but no warranty, express or implied, is given nor is freedom from any patent
`owned by The Dow Chemical Company or by others to be inferred. Inasmuch as any assistance furnished by Dow with reference
`to the proper use and disposal of its products is provided without charge, Dow assumes no obligation or liability therefor.
`
`THE DOW CHEMICAL COMPANY • DESIGNED PRODUCTS DEPARTMENT • MIDLAND MICHIGAN 48640
`
`Printed in U.S.A.
`
`~
`
`Form No. 192-689-79
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 49/86
`
`

`

`Revised 2/79
`
`6• 8
`
`Effect of Additives on Viscosity of 1% Solutions of METHOCEL Cellulose Ether
`
`Trademark
`
`%
`Additive
`
`Producer
`
`Description
`
`Increase in Viscosity of METHOCEL Brands
`
`A
`
`E
`
`F
`
`227
`
`1863
`
`908
`
`145
`
`104
`
`94
`
`K
`
`36
`
`53
`
`J
`
`0
`
`- 5
`
`- 1
`
`-5
`
`- 80
`11
`
`75
`6
`
`11
`
`- 2
`8
`
`99
`4
`
`- 58
`10
`
`- 81
`0
`
`41
`8
`
`30
`36
`
`26
`
`34
`- 1
`
`30
`50
`
`22
`
`- 68
`4
`
`- 92
`- 5
`
`40
`4
`
`35
`42
`
`18
`
`45
`5
`
`29
`2
`
`10
`
`5
`
`5
`
`57
`
`22
`
`104
`
`100
`
`124
`
`105
`
`184
`
`109
`
`36
`
`71
`
`122
`
`132
`
`149
`
`168
`
`5
`
`- 8
`
`- 10
`
`2
`
`4
`
`2080
`
`5845
`
`2798
`
`107
`
`25
`
`10
`
`10
`
`10
`1
`
`Coneo AA5-35S
`
`Coneo Sulfate EP
`
`Miranol C2M Cone.
`
`Miranol L2MSF
`
`Miranol 2MCT
`Modified
`
`Miranol HM Cone.
`
`Polystep 8-11
`
`Quaternary 0
`
`Span 60
`
`Teepol610
`
`Triton CQ 400
`
`Tween 20
`
`Ultrawet 30 DS
`
`Sodium dodecyl
`Continental
`Chemical Company benzene sulfonate
`Continental
`Diethanolamine
`Chemical Company lauryl sulfate
`Dicarboxylated
`Miranol Chemical
`imidazoline derivative
`Co. Inc.
`of coconut fatty acid
`
`Miranol Chemical Dicarboxylated
`Co., Inc.
`imidazoline derivative
`of tall oil fatty acid
`
`Miranol Chemical
`Co., Inc.
`
`Polyoxyethylene
`(3)tridecyl sulfate
`salt of a dicarboxylated
`imidazoline derivative
`of coconut fatty acid
`
`Miranol Chemical Monocarboxylated
`imidazoline derivative
`of lauric acid
`
`Stepan
`Chemical Co.
`Geigy Chemical
`Corp.
`
`Ammonium lauryl
`ethoxylate (4) sulfate
`Quaternary
`ammonium
`imidazoline
`derivative
`Sorbitan
`monostearate
`Secondary sodium
`alkyl sulfonate
`Stearyl dimethyl
`benzyl ammonium
`chloride
`Polyoxyethylene (20)
`ICI United
`sorbitan monolaurate
`States, Inc.
`ARCO Chemical Co. Sodium linear
`alkylate sulfonate
`
`ICI America, Inc.
`
`Shell Chemicals
`UK Ltd.
`Rohm & Hass Co.
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 50/86
`
`

`

`SOLUTION
`RHEOLOGY OF
`METHOCEL SOLUTIONS
`Rheology, defined as the "science of deformation and
`flow of matter," plays an important role in many practi(cid:173)
`cal applications, such as paint, cosmetics, food prod(cid:173)
`ucts, and many more, where modification of flow
`behavior is essential. A Newtonian fluid is one whose
`viscosity is independent of shear rate (or velocity gra(cid:173)
`dient of flow). In actual practice many systems exhibit
`non-Newtonian flow behavior where apparent viscosity
`may decrease (pseudoplastic) or increase (dilatant) with
`increasing rate of shear. These behaviors differ from
`time dependent viscosity changes where viscosity may
`
`decrease (thixotropy) or increase (rheopexy) with time
`at a constant rate of shear.
`
`Rheology of an aqueous solution of METHOCEL is
`affected by its molecular weight, concentration, tem(cid:173)
`perature and by the presence of other solutes. In gen(cid:173)
`eral, at a temperature below the incipient gelation
`temperature, aqueous solutions of METHOCEL exhibit
`pseudoplastic flow. Pseudoplasticity increases with in(cid:173)
`creasing molecular weight or concentration. However at
`very low shear rates, all METHOCEL cellulose ether
`solutions appear to be Newtonian and the shear rate,
`below which the solution becomes Newtonian, in(cid:173)
`creases with decreasing molecular weight or concentra(cid:173)
`tion. The two figures on this sheet demonstrate those
`properties (see also page 6•8).
`
`Apparent Viscosity vs. Shear Rate Curves for 2%Aqueous Solutions of METHOCEL at 20°C
`
`~ 4000
`
`400
`
`100
`
`...... """'
`- ...... ~
`~scl;r '
`-~
`--- loo...
`
`.....
`
`1 . . .
`
`I"'"
`
`......
`
`~
`
`-,.
`
`~ ~ ~
`
`...
`
`10000
`
`w
`en
`i5 a.
`fi 1000
`w
`c.,)
`~-
`en
`c
`c.,)
`en >
`1-z
`w
`I:IC 100
`"' a.
`a. "'
`
`10
`
`0.1
`
`Note: Numbers on curves indicate viscosity types
`© 1974, 1978, The Dow Chemical Company
`
`--1-
`
`25
`
`100
`10
`SHEAR RATE, SEC.'1
`
`1000
`
`NOTICE- This information is presented in good faith, but no warranty, express or implied, is given nor is freedom from any patent
`owned by The Dow Chemical Company or by others to be inferred. Inasmuch as any assistance furnished by Dow with reference
`to the proper use and disposal of its products is provided without charge, Dow assumes no obligation or liability therefor.
`
`THE DOW CHEMICAL COMPANY • DESIGNED PRODUCTS DEPARTMENT • MIDLAND MICHIGAN 48640
`
`Printed in U.S.A.
`
`~
`
`Form Nn 1~?-RRR -7R
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 51/86
`
`

`

`SOLUTION
`
`Apparent Viscosity vs. Shear Rate Curves for Aqueous Solutions of 4000 CPS Grade METHOCEL
`at Different Concentrations at 20°C
`
`10000
`
`1000
`
`100
`
`1.1.1 en
`6
`a..
`i=
`z
`1.1.1
`C,)
`~-
`en
`Q
`C,)
`
`en > ....
`z 1.1.1
`a: cr: a.. a.. cr:
`
`10
`
`0.1
`
`-
`
`1-1-
`
`- ........... ......
`
`I'
`............ ......
`r--
`
`- ~ ~·
`
`r""' ....
`
`2%
`
`' 1.5%
`
`......
`
`"""
`
`1%
`
`......... r--.
`~'t-o
`
`-
`
`0.5%
`
`r- ~~-
`
`"~·
`...... ..
`
`.......... r...... ~~
`
`10
`
`100
`
`1000
`
`SHEAR RATE, SEC."1
`
`Below the incipient gelation temperature (for example
`at 20°C), the rheology of solutions of METHOCEL in
`water is not affected by the type or degree of substitu(cid:173)
`tions, i.e. the same viscosity grade A, E, F, K, or J
`products will exhibit identical viscosity-shear rate
`curves as long as the concentration and temperatures
`are kept constant.
`
`Upon heating, a solution of METHOCEL forms three
`dimensional gel structure and exhibits highly thix(cid:173)
`otropic flow. At high concentrations, a low-viscosity
`type METHOCEL may also be thixotropic even. below
`the gelation temperature.
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 52/86
`
`

`

`SOLUTION
`
`heating rate will result in an apparently high gel
`temperature.
`
`6 •11
`
`The Table shows the approximate gelation temperature
`for 2% aqueous solution of each brand of METHOCEL
`cellulose ether products. The lower Figure on page 6•12
`shows the relationship between gelation temperature
`and concentration for A, E and F type METHOCEL
`cellulose ethers.
`
`Approximate Gel Points of METHOCEL cellulose
`Ether Products (2% aqueous solution)
`
`Brand
`
`Gelation Temperatureoc
`
`THERMAL GELATION
`IN AQUEOUS MEDIA
`METHOCEL cellulose ether products possess unique
`solubility properties in aqueous media. These products
`are insoluble and therefore dispersible in water that has
`been heated above a certain specific temperature. Below
`those temperatures the solvation and solubility of
`METHOCEL cellulose ether products increase as the
`temperature is lowered.
`Aqueous solutions of METHOCEL cellulose ethers when
`heated will gel at temperatures that are specific for each
`type. These gels are completely reversible in that they
`are formed upon heating yet will liquify upon cooling.
`This unique thermal gelation of aqueous solution of
`METHOCEL cellulose ether is a valuable property for
`many end uses.
`The gelation phenomenon of aqueous solution of
`METHOCEL cellulose ether has been postulated to be
`primarily caused by the hydrophobic interaction be(cid:173)
`tween molecules containing methoxyl groups. In a solu(cid:173)
`tion state at lower temperatures, molecules are hydrated
`and there is little polymer-polymer interaction other
`than simple entanglement. As the temperature is in(cid:173)
`creased, the molecules gradually lose their water of
`hydration as reflected by decrease in viscosity.
`Eventually when a sufficient but not complete dehydra(cid:173)
`tion of the polymer occurs, a polymer-polymer associa(cid:173)
`tion takes place and the system approaches an infinite
`network structure as reflected by a sharp rise in viscosity.
`The behavior of a typical solution of METHOCEL cel(cid:173)
`lulose ether, as the temperature is increased and subse(cid:173)
`quently cooled, is shown in the figure to the right. The
`upper figure on page 6•10 is a typical Arhenius plot of
`natural log viscosity vs reciprocal of absolute tempera(cid:173)
`ture showing deviation from linearity, indicating initia(cid:173)
`tion of polymer association.
`The specific thermal gelation temperature is governed
`by the nature and quantity of the substituent groups
`attached to the anhydroglucose ring and will thus vary
`with each type of cellulose ether. For a specific type of
`METHOCEL cellulose ether, there is little or no variation
`of gel temperature on changing viscosity of the grade.
`For all brands, increasing the concentration will result in
`lowering the thermal gelation temperature. Accurate
`measurement of gelation temperature is very difficult
`because it is a function of the rate of heating and the rate
`of shear during the viscosity measurement, and is also a
`function of temperature. A high rate of shear and fast
`© 1978, The Dow Chemical Company
`-Continued
`NOTICE- This information is presented in good faith. bul no warranty, express or implied, is given nor is freedom from any palent
`owned by The Dow Chemical Company or by olhers lo be inferred. Inasmuch as any assistance furnished by Dow with reference
`to Jhe proper use and disposal of ils producls is provided without charge, Dow assumes no obligation or liability therefor.
`
`A
`HB
`F
`E
`J
`K
`
`48
`49
`54
`56
`56
`70
`
`Gelation Of 2% Aqueous Solution Of METHOCEL
`A 100 On Heating @ 0.25"C I min Rate
`
`200 r----------------.
`Rate Of Shear = 86 sec-1
`
`a.
`u
`.~ :g
`Ill >
`
`u
`
`160
`
`120
`
`40
`
`I .. ~ G I •
`
`nc1p1ent e at1on
`Temperature
`
`10
`
`20
`
`50
`40
`30
`Temperature, oc
`
`60
`
`70
`
`THE DOW CHEMICAL COMPANY • DESIGNED PRODUCTS DEPARTMENT • MIDLAND MICHIGAN 48640
`
`Printed in U.S.A.
`
`~
`
`Fnrm Nn 1q?-flR7-7R
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 53/86
`
`

`

`Viscosity- Temperature Relationship for 2% Aqueous Solution of METHOCEL A 100
`at a Shear Rate of 86 sec1
`
`In "'I Viscosity, cP
`5.1 -160
`5
`
`-140
`
`4.9
`
`4.8
`
`4.7
`
`4.6
`
`4.5
`
`4.4
`
`4.3
`4.2
`
`4.1
`
`4
`
`3.7
`
`-120
`
`-100
`
`r- 90
`
`1-- 80
`
`-70
`
`-60
`
`50
`
`-
`...__ 40 I
`
`60
`
`3
`
`\
`~
`_\
`/
`\
`/f
`\
`J/
`\
`/
`..J..
`1~/
`y //t
`
`30
`
`3.1
`
`3.2
`
`3.3
`Temperature
`
`I
`
`/ ~
`
`/
`
`/
`
`/
`
`/
`
`20
`
`I
`
`3.4
`
`10
`
`1-oc
`
`3•5
`
`._ _l_ X 1()3
`T
`
`•
`
`Incipient Gelation Temperature
`Of Different METHOCEL Products
`As A Function Of Concentration
`
`Gel Strength and Texture
`The texture and the stength of gel produced upon
`heating aqueous solutions of METHOCEL cellulose ether
`varies with the type, viscosity grade and the concentra(cid:173)
`tion of METHOCEL used. If a manufacturer wants a
`thermogelling substance to set with a slight elevation of
`temperature and give strong elastic gel, he uses
`METHOCEL A cellulose ether. If he wants a softer, non
`rubbery gel, he uses ForE type METHOCEL cellulose
`ethers. For applications in which only a mushy ap(cid:173)
`pearance is desirable on heat.ing, METHOCEL K or
`METHOCEL J will be the product of choice.
`
`In general the strength of the gel increases sharply on
`increasing molecular weight and gradually becomes
`constant at or above viscosity grade of 400 cP. Gel
`strength also increases with increasing concentration .
`The next table shows the typical gel strength of some of
`the METHOCEL cellulose ether products.
`
`Agitation affects the strength and apparent temperature
`of gelation; continued rapid agitation during gelation
`-Continued
`
`•
`
`I
`I
`I
`-~
`METHOCEL E-
`~ ......... ....... ......
`Slope =-1.0
`.... ~ ... L
`........
`I
`I
`'
`~ ....
`.......
`'
`
`~
`
`METHOCEL F
`-,rope=-1.77
`'1 .....
`I
`
`'
`
`~
`
`60
`
`~ 55
`e·
`! 50
`
`CD
`Q.
`E 45
`t!!
`g
`'i 40
`'ii
`c:J 35
`1:
`CD
`'ii 30
`
`·u .s
`
`-..........
`~ ' METHOCEL A
`' """""'
`
`~ope =-2.33
`
`6
`
`7 8 9
`
`10
`
`11
`
`12
`
`25
`
`1
`
`2 3 4 5
`
`Concentration, Wt %
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 54/86
`
`

`

`may break down the gel structure and alter both the
`texture and strength of the gel. For the maximum
`development of gel strength under quiescent condition,
`heat the solution above the gelation temperature for
`about 3 hours.
`
`Gel Strength of Different METHOCEL Brand
`Cellulose Ethers as Measured by a Penetrometer.
`
`METHOCEl Brand
`
`Gel Strength, g I cm2
`of 2"/o Solution at 65°C
`
`METHOCEL A15
`METHOCEL A25
`METHOCEL A50
`METHOCEL A100
`METHOCEL A4C
`METHOCEL A4M
`
`METHOCEL F4M
`METHOCEL E4M
`METHOCEL K4M
`METHOCEL J4M
`
`400
`1000
`2000
`3500
`5000
`5000
`
`1500
`> 500
`Not measurable
`Not measurable
`
`6.13
`
`Effect of Additives
`on Thermal Gelation
`Additives may either increase or decrease the thermal(cid:173)
`gel temperature. A particular concentration of one
`additive may increase the gel temperature and the
`same concentration of a different additive may de(cid:173)
`crease it. Decrease in gel temperature is a function of
`the ions present: the higher the charge on the ion, the
`greater will be the decrease in the thermal gel tem(cid:173)
`perature. If a manufacturer requires a high thermal gel
`temperature and plans to use additives that would
`reduce that temperature, he uses a METHOCEL cel(cid:173)
`lulose ether product gelling at a temperature higher
`than the temperature he requires. As the concentration
`of a gel-causing additive increases, the thermal gel
`temperature decreases.
`
`A list of representative additives and their effect on
`various METHOCEL cellulose ether products is shown
`in the following table.
`
`Effect on Gelation Temperature Noted With Additives to 2 Percent
`Solutions ofMETHOCEL Cellulose Ether
`
`Additive
`Compound
`
`%
`
`METHOCEL A 15C
`(1,500 cps}
`oc
`
`OF
`
`METHOCEL F15C*
`(1,500 cps}
`oc
`OF
`
`METHOCEL K4M
`(4,000 cps}
`oc
`OF
`
`METHOCEl J5M
`(5,000 cps}
`oc
`OF
`
`CONTROL
`(no additivel
`5
`5
`3
`5
`2.5
`5
`2.0
`5
`20
`20
`20
`20
`20
`
`NaCI
`MgCI2
`1
`FeCI3
`N~zso.
`AI 2(SO.I3
`Na2C031
`Na3P04
`Sucrose
`Sucrose
`Sorbitol
`Glycerine'
`Ethanol
`Polyethylene
`Glycol4001
`Propylene
`Glycol'
`
`20
`
`50
`33
`42
`42
`
`32
`51
`44
`30
`34
`>75
`52
`
`59
`
`122
`91
`107
`107
`Salted out
`Salted out
`Salted out
`89
`124
`111
`86
`93
`>167
`126
`
`138
`
`63
`41
`52
`53
`
`45
`
`42
`66
`59
`46
`60
`>75
`>80
`
`>80
`
`145
`105
`125
`127
`Salted out
`113
`Salted out
`107
`151
`138
`115
`140
`>167
`>176
`
`85
`59
`67
`76
`
`48
`
`52
`84
`61
`48
`65-70
`>75
`>80
`
`185
`138
`153
`169
`Salted out
`118
`Salted out
`125
`183
`142
`118
`149-158
`>167
`> 176
`
`62
`42
`50
`53
`
`41
`
`43
`60
`53
`39
`55
`>78
`>78
`
`143
`107
`122
`127
`Salted out
`106
`Salted out
`109
`140
`127
`102
`131
`>172
`>172
`
`>176
`
`>80
`
`>176
`
`>78
`
`>172
`
`• a special viscosity grade made by blending
`Of the compounds in the table, sucrose, ethanol, and the two polyglycols raise the gelation temperature.
`Unlisted additional compounds that raise the thermal gel temperature include Armac2, Armac HDT2, Hyamine
`16223 alkali metal thiocyanates and urea.
`1 The Dow Chemical Company
`2 Armour and Company
`3 Rohm & Haas Company
`
`-Continued
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 55/86
`
`

`

`6 •14
`
`SOLUTION
`Gel Point Raising Additives
`The effectiveness of a gel point raising additive on the
`thermal gel point will vary with the chemical nature of
`the additive and with the brand of METHOCEL cellulose
`ether product. For example, a particular additive,
`propylene glycol, that increases the thermal gel tem(cid:173)
`perature of a solution of METHOCEL A or METHOCEL HB
`cellulose ether product by 4°C will increase the thermal(cid:173)
`gel temperature of a solution of METHOCEL F cellulose
`ether product by 10°C, and that of a solution of
`METHOCEL K cellulose ether product by more than 20°C,
`
`The increase in thermal gel point of a solution of
`METHOCEL is in direct proportion to the increase in
`concentration of the gel point raising additive. A 2
`percent aqueous solution of METHOCEL A cellulose
`
`ether product containing a 10 percent concentration
`by volume of ethanol will gel at a temperature 1 0°C
`higher than a pure aqueous solution of METHOCEL A.
`A 15 percent concentration of ethanol increases the
`gel temperature 15°C above the gel temperature of an
`aqueous solution of METHOCEL A.
`
`A solution of METHOCEL F cellulose ether product
`containing a 10 percent concentration of propylene
`glycol gels 6°C higher than does a pure aqueous
`solution, whereas a solution of METHOCEL F cellulose
`ether product containing 15 percent concentration of
`propylene glycol gels 11 °C higher than does a pure
`aqueous solution. The following figures show the
`relation between concentration of an additive and the
`thermal gel temperature of representative METHOCEL
`cellulose ether products.
`
`Effect of Ethanol on Thermal Gel
`Temperature (2 Percent Solutions)
`
`Effect of Propylene Glycol on Thermal Gel
`Temperature (2 Percent Solutions)
`
`25
`
`u •
`ci. 20
`e
`~
`"i
`c:l
`
`15
`
`;;; e
`! 10
`.. ..5
`
`.5
`~
`ID
`I!!
`
`5
`
`(4,000 cps)
`
`45
`
`36
`
`27
`
`9
`
`"i e
`18 !
`Ill ..
`
`... .
`ci. e
`t!!
`"i
`c:l
`
`.5
`
`I!!
`~
`
`METHOCEL F4M
`
`25
`
`u . ci 20
`
`e
`~
`"i
`c:l
`~
`! 10
`.5
`Ill
`..
`ID
`I!!
`..5
`
`15
`
`5
`
`(4,000 cps)
`
`0
`
`5
`
`10
`
`15
`
`0
`
`20
`
`Ethanol, % by Volume
`
`0
`
`0
`
`5
`
`10
`
`15
`
`20
`
`Propylene Glycol, % by Volume
`
`... .
`t
`~
`"i
`c:l
`
`"i e .. !!=
`!'! .. ..5
`
`.5
`Ill
`
`45
`
`36
`
`27
`
`18
`
`9
`
`0
`
`•
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 56/86
`
`

`

`Blending Chart for METHOCEL E5 and E15 Pre(cid:173)
`mium (USP) (5% Concentration in Water)
`
`6 •15
`
`SOLUTION
`Factors Affecting Use of Solutions
`Recommended
`Concentrations for Coating Solutions
`The concentration for METHOCEL E Premium
`(USP) products-for aqueous tablet coating-is
`dependent on the viscosity and equipment being
`used for spray application. For example: if desired
`viscosity of the complete coating solution is
`150-200 centipoises, METHOCEL E products in
`water should provide that viscosity at the following
`concentrations:
`
`200
`
`150
`
`100
`
`...
`J;j
`..
`@)
`a.
`..
`.. ..
`.~
`:;
`
`200
`
`-
`
`150
`
`100
`
`50
`
`100% of
`METHOCEL E15
`
`<
`iii"
`n
`
`.. ..
`~
`.,
`n
`®
`...
`~
`
`40
`
`60
`
`80
`
`100
`
`60
`
`40
`
`20
`
`0
`
`%, METHOCEL E5
`
`Concentration
`wt/wt
`
`100% of
`METHOCEL E5
`
`0
`
`20
`
`%, METHOCEL E15
`100 80
`
`Product
`
`METHOCEL ES
`Premium
`
`METHOCEL E15
`Premium
`
`METHOCEL ESO
`Premium
`
`7.5-10%
`
`4.5-6.5%
`
`2.3-3.5%
`
`Blending Chart for METHOCEL E5 and E15 Pre(cid:173)
`mium (USP) (10% Concentration in Water)
`
`Note: With addition of other ingredients (pig(cid:173)
`ments, lakes, dyes, plasticizer, etc.), viscosity may
`have to be adjusted accordingly.
`The low viscosity of METHOCEL E5 Premium per(cid:173)
`mits higher solids in the coating solution and
`consequently less water has to be removed. How(cid:173)
`ever, this lower viscosity product gives films hav(cid:173)
`ing lower elongation. Higher viscosity METHOCEL
`E15 and METHOCEL E50 cellulose ethers result in
`tougher, stronger films. Use of blends of different
`viscosity METHOCEL E products can achieve de(cid:173)
`sired balances of viscosity, solids content, and film
`strength that are not as readily achieved when one
`METHOCEL E product is employed.
`Formulation Properties
`Properly formulated aqueous dispersions of METHOCEL
`E premium products should be:
`• excellent film-formers
`• noncaloric
`• nonallergenic
`• non-nutritive
`• more resistant to microorganisms than are natural
`gums
`© 1978, The Dow Chemical Company
`
`...
`J;j
`a. ..
`@)
`.~ .. .. .. :;
`
`100% of
`METHOCEL E5
`
`:5 .. n .. 2!.
`
`;t
`
`n .,
`®
`~ ...
`
`%, METHOCEL E15
`
`0
`
`20
`
`40
`
`60
`
`80 100
`
`100 80
`
`60
`
`40
`
`20
`
`0
`
`%, METHOCEL E5
`
`-Continued
`
`NOTICE- This information is presented in good faith. but no warranty. express or 1mphed, IS g1ven nor IS freedom from any patent
`owned by The Dow Chemical Company or by others to be inferred. Inasmuch as any assistance furnished by Dow with reference
`to the proper use and disposal of its products is provided without charge, Dow assumes no obligation or liability therefor.
`
`THE DOW CHEMICAL COMPANY • DESIGNED PRODUCTS DEPARTMENT • MIDLAND MICHIGAN 48640
`
`Printed in U.S.A.
`
`~
`
`• Tr!:lrf.Orn!:llrl..- nf Tho nn\AI f"hornif"!:lll rnrnn!:lln\1
`
`Form No. 192-688-78
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 57/86
`
`

`

`6 •16
`
`SOLUTION
`Starting Point Formulations
`100% Aqueous Coating Systems for Tablets
`
`................. #3
`......... #2
`Formulation ............. .. . ........... ............. #1
`METHOCEL E5
`METHOCEL E15
`METHOCEL E50
`
`Polymer, %1 • • • . . • . • • • • • • • • . . • . . . • • • • • • • • • • •
`Plasticizer, % . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Pigments, 0/o
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Potable Water, % . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Solids, % . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`9.0
`2.0
`7.0
`82.0
`18.0
`
`5.0
`1.1
`3.85
`91.05
`8.95
`
`3.0
`0.66
`2.33
`94.01
`5.99
`
`1 o/o by weig ht
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2017 - 58/86
`
`

`

`DEFOAMERS FOR
`AQUEOUS SOLUTIONS
`
`The foaming of METHOCEL cellulose ether solutions is
`easily controlled by using foam stabilizers and de(cid:173)
`foamers. The defoamers listed in the table below have
`been efficient in use; other commercial defoamers could
`work as well but should be tested for performance. The
`concentration required for defoaming with any of these
`agents is 25-1000 ppm based on solution weights. De(cid:173)
`foamer concentrations should be kept to the minimum
`required, because these materials are general