1
`
`AMN1020
`
`Mylan (IPR2019-01095) MYLAN1020, p. 001
`
`

`

`CALIFORNIA JURAT
`
`See Attached Document.
`
`A notary public or other officer completing this
`certificate verifies only the identity of the
`individual who signed the document to which this
`certificate is attached, and not the truthfiilness,
`
`accuracy, or validity of that document.
`
`State of California
`
`County of San Francisco
`
`Subscribed and sworn to (or affirmed) before me on
`this
`
`HQ
`
`day of Ofidggv"
`
`, Zglg ,by
`
`Christopher Butler,
`
`
`
`LVNN~~
`
`Notary Public - California
`
`San Francisco County
`
`
`mmission # 2172222
`CO
`‘res
`
`
`proved to me on the basis of satisfactory evidence to be
`the person who appeared before me.
`
` Signature: 0
`
`Mylan (11311201901095) MYLAN1020, p. 002
`2
`
`2
`
`Mylan (IPR2019-01095) MYLAN1020, p. 002
`
`

`

`
`Exhibit A
`
`3
`
`Mylan (IPR2019-01095) MYLAN1020, p. 003
`
`

`

`https://web.archive.org/web/20120402124354/http://www.lubrizol.com:80/Pha
`rmaceutical-Ingredients/Documents/Technical-Data-Sheets/TDS-730-Viscosity-
`Carbopol-in-Aqueous-Systems.pdf
`
`4
`
`Mylan (IPR2019-01095) MYLAN1020, p. 004
`
`

`

`
`
`
`
`
`
`
`TECHNICAL DATA SHEET
`TDS-730
`Edition: August 13, 2010
`Original Date: November 24, 2009 / January 27, 2010
`
`
`Viscosity of Carbopol®* Polymers in
`Aqueous Systems
`
`Introduction
`Carbopol® polymers can be used to develop semisolid and oral liquid formulations with a wide range of flow
`and rheological properties (Figure 1). The polymers are highly efficient thickeners, suspending agents and
`stabilizers at low usage levels (0.1 - 3.0 wt%).
`
`Figure 1: Flow Properties of Carbopol® Polymers, Neutralized Dispersions
`
`
`
`
`
`
`
`
`Low
`Long (Pourable)
`
`Polymer Crosslink Density: High/Medium
` Short
`Flow Property:
`
`
`All Carbopol® polymers are high molecular weight, crosslinked polyacrylic acid polymers. The main
`differences among the polymers are the crosslinker type and density and solvent used to synthesize the
`polymer. A description of the polymers featured in this document is shown in Tables 1A and 1B. Please
`refer to Bulletin 1- Polymers for Pharmaceutical Applications for a complete list of polymers.
`
`
`Table 1A: Carbopol® Polymers Overview
`
`Carbopol®
`Polymer Type Crosslink
`Polymerization
`Recommended
`Density
`Solvent
`Applications
`Polymer
`Homopolymer
`Low
`Ethyl Acetate
`Oral / Topical
`971P NF
`Homopolymer
`Medium
`Ethyl Acetate
`Oral / Topical
`974P NF
`Cosolvent1
`Homopolymer
`High
`Topical
`980 NF
`Homopolymer
`Medium
`Cosolvent
`Topical
`5984 EP
`Interpolymer
`Medium
`Cosolvent
`Topical
`ETD 2020 NF
`Interpolymer
`High
`Cosolvent
`Topical
`Ultrez 10 NF
`1 Cosolvent is a mixture of ethyl acetate and cyclohexane.
`
`
`Lubrizol Advanced Materials, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800.379.5389 or 216.447.5000Lubrizol Advanced Materials, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800.379.5389 or 216.447.5000
`
`The information contained herein is believed to be The information contained herein is believed to be
`
`Materials, Inc.’s direct control. THE SELLER MAKES NO Materials, Inc.’s direct control. THE SELLER MAKES NO
`
`equipment used commercially equipment used commercially
`
`in processing in processing
`
`these these
`
`reliable, but no reliable, but no
`
`representations, guarantees or representations, guarantees or
`
`WARRANTIES, EXPRESS OR IMPLIED, INCLUDING, WARRANTIES, EXPRESS OR IMPLIED, INCLUDING,
`
`materials, no warranties or guarantees are made as to materials, no warranties or guarantees are made as to
`
`warranties of any kind are made as to its accuracy, warranties of any kind are made as to its accuracy,
`
`BUT NOT LIMITED TO, THE IMPLIED WARRANTIES BUT NOT LIMITED TO, THE IMPLIED WARRANTIES
`
`the suitability of the suitability of
`
`the products the products
`
`
`for for
`the application the application
`
`suitability for particular applications or the results to be suitability for particular applications or the results to be
`
`OF MERCHANTABILITY AND FITNESS FOR A OF MERCHANTABILITY AND FITNESS FOR A
`
`disclosed. disclosed.
`
` Full-scale Full-scale
`
`testing and end product testing and end product
`
`obtained therefrom. The information is based on obtained therefrom. The information is based on
`
`PARTICULAR PURPOSE. Nothing contained herein is PARTICULAR PURPOSE. Nothing contained herein is
`
`performance are the responsibility of the user. Lubrizol performance are the responsibility of the user. Lubrizol
`
`laboratory work with small-scale equipment and does laboratory work with small-scale equipment and does
`
`to be considered as permission, recommendation, nor to be considered as permission, recommendation, nor
`
`Advanced Materials, Inc. shall not be liable for and the Advanced Materials, Inc. shall not be liable for and the
`
`not necessarily not necessarily
`
`indicate end product performance. indicate end product performance.
`
`as an inducement to practice any patented invention as an inducement to practice any patented invention
`
`customer assumes all risk and liability of any use of customer assumes all risk and liability of any use of
`
`Because of the variations in methods, conditions and Because of the variations in methods, conditions and
`
`without permission of the patent owner. without permission of the patent owner.
`
`handling of any material beyond Lubrizol Advanced handling of any material beyond Lubrizol Advanced
`
`
`
`For further information, please visit www.pharma.lubrizol.comFor further information, please visit www.pharma.lubrizol.com
`Lubrizol Advanced Materials, Inc. is a wholly owned subsidiary of The Lubrizol Corporation
`* Trademark owned by The Lubrizol Corporation
`© Copyright 2010 / The Lubrizol Corporation
`
`
`
`
`Aqueous Gel Viscosity
`Low
`Medium - high
`Very high
`Medium - high
`Medium - high
`Very high
`
`
`
`5
`
`Mylan (IPR2019-01095) MYLAN1020, p. 005
`
`

`

`
`
`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 2 of 10
`
`Europe (Ph. Eur.)
`Carbomers
`Carbomers
`Carbomers
`Carbomers
`---
`---
`
`Japan (JPE)1
`Carboxyvinyl Polymer
`Carboxyvinyl Polymer
`Carboxyvinyl Polymer
`Carboxyvinyl Polymer
`---
`---
`
`Table 1B: Compendial Status of Polymers
`
`United States USP/NF*
`Product Trade Name
`Carbopol® 971P NF Polymer
`Carbomer Homopolymer Type A
`Carbopol® 974P NF Polymer
`Carbomer Homopolymer Type B
`Carbopol® 980 NF Polymer
`Carbomer Homopolymer Type C
`Carbopol® 5984 EP Polymer
`Carbomer Homopolymer Type B
`Carbopol® ETD 2020 NF Polymer Carbomer Interpolymer Type B
`Carbopol® Ultrez 10 NF Polymer
`Carbomer Interpolymer Type A
`* USP/NF after 2006
`
`Brookfield Viscosity of Carbopol® Polymer Dispersions
`
`Carbopol® polymers must be neutralized in order to achieve maximum viscosity. Once a neutralizer is
`added to the dispersion, thickening gradually occurs. Maximum viscosity is typically achieved at a pH of
`6.0 - 7.0.
`
`The viscosity of Carbopol® polymers will begin to decrease at a pH of 9.0 and higher. This is caused by the
`presence of excess electrolytes which affect the electrostatic repulsion of the ionized carboxylic groups. In
`order to obtain high viscosity at pH values below 5 and above 9, an increased concentration of Carbopol®
`polymer is recommended. Additionally, use of a low concentration of polymer at low pH values should be
`avoided in an effort to achieve a robust formulation.
`
`Brookfield viscosity measurements were obtained for aqueous dispersions of several Carbopol® polymers
`at concentrations of 0.2 - 2.0 wt. %. The general behavior of each polymer is shown in Figures 2 - 7 based
`on the data for one lot of each polymer. The dispersions were tested as prepared (conventionally
`represented as pH 3.0) or after neutralization with sodium hydroxide solution to pH 4.0 - 7.0. An increase
`in polymer concentration results in an increase in viscosity. In general, a pH plateau is achieved more
`readily with higher concentrations of Carbopol® polymers.
`
`
`Figure 2: Effect of pH and Concentration on the Viscosity of Carbopol® 971P NF Polymer Dispersion
`
`
`0.2% 971P NF
`0.5% 971P NF
`1.0% 971P NF
`2.0% 971P NF
`
`15000
`
`12000
`
`9000
`
`6000
`
`3000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`
`1 Based on customer request, Lubrizol certifies select lots of product against the JPE Carboxyvinyl Polymer Monograph
`
`
`
`6
`
`Mylan (IPR2019-01095) MYLAN1020, p. 006
`
`

`

`
`Figure 3: Effect of pH and Concentration on the Viscosity of Carbopol® 974P NF Polymer Dispersion
`
`
`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 3 of 10
`
`0.2% 974P NF
`0.5% 974P NF
`1.0% 974P NF
`2.0% 974P NF
`
`100000
`
`80000
`
`60000
`
`40000
`
`20000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`
`
`
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`Figure 4: Effect of pH and Concentration on the Viscosity of Carbopol® 980 NF Polymer Dispersion
`
`
`0.2% 980 NF
`0.5% 980 NF
`1.0% 980 NF
`2.0% 980 NF
`
`100000
`
`80000
`
`60000
`
`40000
`
`20000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`
`7
`
`Mylan (IPR2019-01095) MYLAN1020, p. 007
`
`

`

`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 4 of 10
`
`
`
`Figure 5: Effect of pH and Concentration on the Viscosity of Carbopol® 5984 EP Polymer Dispersion
`
`
`0.2% 5984 EP
`0.5% 5984 EP
`1.0% 5984 EP
`2.0% 5984 EP
`
`75000
`
`60000
`
`45000
`
`30000
`
`15000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`
`
`
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`Figure 6: Effect of pH and Concentration on the Viscosity of Carbopol® ETD 2020 NF Polymer Dispersion
`
`
`0.2% ETD 2020 NF
`0.5% ETD 2020 NF
`1.0% ETD 2020 NF
`2.0% ETD 2020 NF
`
`120000
`
`100000
`
`80000
`
`60000
`
`40000
`
`20000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`
`8
`
`Mylan (IPR2019-01095) MYLAN1020, p. 008
`
`

`

`
`Figure 7: Effect of pH and Concentration on the Viscosity of Carbopol® Ultrez 10 NF Polymer Dispersion
`
`
`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 5 of 10
`
`0.2% Ultrez 10 NF
`0.5% Ultrez 10 NF
`1.0% Ultrez 10 NF
`2.0% Ultrez 10 NF
`
`120000
`
`100000
`
`80000
`
`60000
`
`40000
`
`20000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`A comparison of the viscosity of 1.0 wt. % aqueous dispersions of several topical grades of Carbopol®
`polymers is shown in Figure 8.
`
`
`Figure 8: Effect of Polymer Type on the Viscosity of 1.0% Dispersions – Topical Products
`
`
`1.0% 980 NF
`1.0% Ultrez 10 NF
`1.0% ETD 2020 NF
`1.0% 5984 EP
`
`75000
`
`60000
`
`45000
`
`30000
`
`15000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`2
`
`3
`
`4
`
`
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`9
`
`Mylan (IPR2019-01095) MYLAN1020, p. 009
`
`

`

`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 6 of 10
`
`
`The effect of polymer type and concentration on the viscosity at pH 6.0 is represented in Figure 9 for
`several topical grades of Carbopol® polymers.
`
`Figure 9: Effect of Polymer Type and Concentration on the Viscosity at pH 6.0 – Topical Products
`
`
`980 NF
`Ultrez 10 NF
`ETD 2020 NF
`5984 EP
`
`120000
`
`100000
`
`80000
`
`60000
`
`40000
`
`20000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`0
`
`0.5
`
`1.5
`1
`concentration (%)
`
`2
`
`2.5
`
`
`
`A comparison of the viscosity of oral grade Carbopol® 971P NF and 974P NF polymers at various pH levels
`and concentrations is shown in Figure 10.
`
`
`Figure 10: Effect of pH and Concentration on the Viscosity of Carbopol® 971P NF and 974P NF Polymer Dispersions
`
`0.2% 971P NF
`0.5% 971P NF
`1.0% 971P NF
`2.0% 971P NF
`0.2% 974P NF
`0.5% 974P NF
`1.0% 974P NF
`2.0% 974P NF
`
`100000
`
`80000
`
`60000
`
`40000
`
`20000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`10
`
`Mylan (IPR2019-01095) MYLAN1020, p. 010
`
`

`

`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 7 of 10
`
`
`Unneutralized dispersions as prepared have an approximate pH range of 2.5 - 3.5 depending on the
`polymer concentration. The unneutralized dispersions have very low viscosities as shown in Figure 11,
`especially for Carbopol® Ultrez 10 NF polymer and Carbopol® ETD 2020 NF polymers.
`
`Carbopol® Ultrez 10 NF polymer and Carbopol® ETD 2020 NF polymers provide excellent versatility in
`processing for topical formulations. Their unique dispersion performance allows the polymers to wet
`quickly, yet hydrate slowly. This minimizes agglomeration, which can be a problem if turbulent mixing is
`
`
`not available during dispersion. Compared with traditional Carbopol® polymers, Carbopol® Ultrez and ETD
`polymers provide dispersions in water that are much lower in viscosity prior to neutralization which enables
`easier handling in mixing tanks and process lines. Once the polymers are neutralized, they are highly
`efficient thickeners.
`
`Figure 11: Effect of Polymer Type and Concentration on the Viscosity of Dispersions as Prepared
`
`
`971P NF
`974P NF
`980 NF
`Ultrez 10 NF
`ETD 2020 NF
`5984 EP
`
`7500
`
`6000
`
`4500
`
`3000
`
`1500
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`0
`
`0.5
`
`1.5
`1
`concentration (%)
`
`2
`
`2.5
`
`
`In aqueous systems, inorganic bases, such as sodium hydroxide or potassium hydroxide, or low molecular
`weight amines and alkanolamines will provide satisfactory neutralization. Figure 12 shows similar
`thickening efficiencies when sodium hydroxide and triethanolamine are used to neutralize a 0.5 wt%
`aqueous dispersion of Carbopol® 980 NF polymer. No significant differences are expected if potassium
`hydroxide is used for neutralization.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`11
`
`Mylan (IPR2019-01095) MYLAN1020, p. 011
`
`

`

`
`Figure 12: Effect of Neutralizer Type on the Viscosity of 0.5% Carbopol® 980 NF Dispersion
`
`
`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 8 of 10
`
`Sodium hydroxide (18%)
`Triethanolamine (99%)
`
`50000
`
`40000
`
`30000
`
`20000
`
`10000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`2
`
`3
`
`4
`
`5
`pH
`
`6
`
`7
`
`8
`
`
`
`Electrolytes tend to reduce the viscosity of Carbopol® polymer based gels. Therefore, a higher
`concentration of polymer should be used to minimize the viscosity loss. In general, the viscosity of lightly
`crosslinked Carbopol® polymer systems is less affected by electrolytes than highly crosslinked Carbopol®
`polymers. (Figure 13).
`
`
`Figure 13: Effect of Salt on the Viscosity of 1.0% Carbopol® 971P NF and 974P NF Polymer Dispersions at pH 6.0
`
`
`971P NF
`974P NF
`
`75000
`
`60000
`
`45000
`
`30000
`
`15000
`
`Brookfield viscosity @ 20 rpm (mPa*s)
`
`0
`
`0
`
`0.25
`
`0.5
`
`0.75
`% NaCl
`
`1
`
`1.25
`
`1.5
`
`
`
`
`
`12
`
`Mylan (IPR2019-01095) MYLAN1020, p. 012
`
`

`

`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 9 of 10
`
`
`Brookfield Yield Value of Carbopol® Polymer Dispersions
`
`Carbopol® polymers are unique in that they provide a wide range of viscosity profiles and have very high
`yield values, even at low concentrations. These combined features enable the formulation of oral or topical
`suspensions that are stable with low levels of polymer.
`
`Yield value is more important than viscosity when determining suspending ability of a vehicle. While
`viscosity can only slow down the rate of sedimentation, a high yield value is necessary to create permanent
`suspensions.
`
`While all Carbopol® polymers are efficient suspending agents, medium/highly crosslinked polymers have
`higher yield value than lightly crosslinked polymers such as Carbopol® 971P NF polymer (Figure 14).
`Refer to TDS-244 to calculate a theoretical yield value for a suspension.
`
`Figure 14: Effect of Polymer Type on the Brookfield Yield Value of Carbopol® Polymer Dispersions at pH 6.0
`
`
`971P NF
`974P NF
`980 NF
`Ultrez 10 NF
`ETD 2020 NF
`5984 EP
`
`20000
`
`15000
`
`10000
`
`5000
`
`Brookfield yield value (dynes/cm2)
`
`0
`
`0
`
`0.5
`
`1.5
`1
`concentration (%)
`
`2
`
`2.5
`
`
`
`The data included represents one lot of each polymer in an aqueous system. The performance of the
`polymers in other conditions (alternative vehicles, coexcipients and active pharmaceutical ingredients)
`might be different. It is recommended that key performance properties be ascertained and regulatory
`considerations be taken into account in the process of formulation development.
`
`Carbopol® polymers have been used in a variety of commercial liquid and semisolid formulations containing
`the active pharmaceutical ingredients (APIs) noted in Table 2. These APIs have been incorporated in a
`variety of dosage forms: solutions, suspensions, emulsions, lotions, creams, gels and toothpaste for
`peroral or topical administration (skin, mucosa - oral, ophthalmic, nasal, rectal, vaginal).
`
`
`
`13
`
`Mylan (IPR2019-01095) MYLAN1020, p. 013
`
`

`

`TDS-730
`Viscosity of Carbopol® Polymers in Aqueous Systems
`Page 10 of 10
`
`Table 2: Commercial Liquid and Semisolid Formulations Containing Carbopol® Polymers
`
`
`
`
`
`(cid:122)(cid:122) Adapalene
`(cid:122)(cid:122) Aescin
`(cid:122)(cid:122) Allantoin
`(cid:122)(cid:122) Amorolfine hydrochloride
`(cid:122)(cid:122) Azelaic acid
`(cid:122)(cid:122) Benzocaine
`(cid:122)(cid:122) Benzoyl peroxide
`(cid:122)(cid:122) Betamethasone dipropionate
`(cid:122)(cid:122) Betaxolol hydrochloride
`(cid:122)(cid:122) Brinzolamide
`(cid:122)(cid:122) Ciclopirox
`(cid:122)(cid:122) Clarithromycin
`(cid:122)(cid:122) Clindamycin
`(cid:122)(cid:122) Clobetasol propionate
`(cid:122)(cid:122) Clocortolone pivalate/ hexanoate
`(cid:122)(cid:122) Clotrimazole
`(cid:122)(cid:122) Crotamiton
`(cid:122)(cid:122) Cyclosporine
`(cid:122)(cid:122) Dexamethasone
`(cid:122)(cid:122) Dexpanthenol
`(cid:122)(cid:122) Domperidone
`(cid:122)(cid:122) Diclofenac
`(cid:122)(cid:122) Diethylamin-Salicylate
`(cid:122)(cid:122) Estradiol
`
`(cid:122)(cid:122) Estriol
`(cid:122)(cid:122) Etofenamate
`(cid:122)(cid:122) Eucalyptus oil
`(cid:122)(cid:122) Extracts (Capsicum, Arnica)
`(cid:122)(cid:122) Fluocinonide
`(cid:122)(cid:122) Fluorouracil
`(cid:122)(cid:122) Fusidic acid
`(cid:122)(cid:122) Ganciclovir
`(cid:122)(cid:122) Glycerin
`(cid:122)(cid:122) Heparin sodium
`(cid:122)(cid:122) Hydrocortisone
`(cid:122)(cid:122) Hydroquinone
`(cid:122)(cid:122) Hydroxyethylsalicylate
`(cid:122)(cid:122) Ichthammol
`(cid:122)(cid:122) Indomethacin
`(cid:122)(cid:122) Isotretinoin
`(cid:122)(cid:122) Ketoconazole
`(cid:122)(cid:122) Ketoprofen
`(cid:122)(cid:122) Lidocaine
`(cid:122)(cid:122) Menthol
`(cid:122)(cid:122) Mesalamine
`(cid:122)(cid:122) Methyl salicylate
`(cid:122)(cid:122) Metronidazole
`(cid:122)(cid:122) Miconazole nitrate
`
`(cid:122)(cid:122) Naftifine hydrochloride
`(cid:122)(cid:122) Nepafenac
`(cid:122)(cid:122) Nevirapine
`(cid:122)(cid:122) Nonoxynol 9
`(cid:122)(cid:122) Nystatin
`(cid:122)(cid:122) Octyl methoxycinnamate
`(cid:122)(cid:122) Permethrin
`(cid:122)(cid:122) Polidocanol)
`(cid:122)(cid:122) Prilocaine
`(cid:122)(cid:122) Progesterone
`(cid:122)(cid:122) Retinol palmitate
`(cid:122)(cid:122) Rimexolone
`(cid:122)(cid:122) Simethicone
`(cid:122)(cid:122) Sodium alginate
`(cid:122)(cid:122) Sodium fluoride
`(cid:122)(cid:122) Sodium hyaluronate
`(cid:122)(cid:122) Testosterone
`(cid:122)(cid:122) Thioridazine
`(cid:122)(cid:122) Timolol maleate
`(cid:122)(cid:122) Tretinoin
`(cid:122)(cid:122) Tyrothricin
`(cid:122)(cid:122) Urea
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`https://web.archive.org/web/20120424165604/http://www.lubrizol.com:80/Pha
`rmaceutical-Ingredients/Documents/Bulletins/Bulletin-21---Formulating-
`Semisolid-Products.pdf
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` PHARMACEUTICAL BULLETIN
`
`
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`Pharmaceutical Bulletin 21
`Edition: May 31, 2011
`Previous Editions: August 15, 2005 / October 29, 2008 / August 11, 2010
`
`
`FFoorrmmuullaattiinngg SSeemmiissoolliidd PPrroodduuccttss
`
`
`
`
`Carbopol®* polymers, Pemulen™* polymers and Noveon®* polycarbophil are some of the most widely
`used excipients for thickening lotions, creams and gels. These polymers are also used to modify the
`rheology of water-based systems and to stabilize multi-phase systems such as emulsions and
`suspensions. Carbopol® polymers have enabled the formulation of topical pharmaceutical products for fifty
`years, and are widely used on a global basis.
`
`The performance of the polymer in semisolid products is maximized when the macromolecule is fully
`swollen. The swelling provides rheology modification, suspending properties and emulsification to the
`topical formulation. Polymer swelling can be accomplished in several ways (neutralization or hydrogen
`bonding).
`
`Carbopol® polymers, Pemulen™ polymers and Noveon® polycarbophil, are polymers of acrylic acid,
`crosslinked with polyalkenyl ethers or divinyl glycol. Each polymer particle is a network structure of
`polymer chains interconnected by crosslinks. Without the crosslinks, the primary particle would be a
`collection of linear polymer chains, intertwined but not chemically bonded. These polymers swell in water
`up to 1,000 times their original volume (and ten times their original diameter) to form gels when
`neutralized. Since the pKa of these polymers is 6±0.5, the carboxylate groups on the polymer backbone
`ionize, resulting in electrostatic repulsion between the negative particles, which extends the molecule,
`adding to the swelling of the polymer.
`
`Thickening by hydrogen bonding is recommended in cases where it is not feasible to increase the pH of
`the final formulation. For more details, see Pharmaceutical Bulletin 5: “Neutralization Procedures”.
`
`
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`Lubrizol Advanced Materials, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800.379.5389 or 216.447.5000Lubrizol Advanced Materials, Inc. / 9911 Brecksville Road, Cleveland, Ohio 44141-3247 / TEL: 800.379.5389 or 216.447.5000
`
`The information contained herein is believed to be The information contained herein is believed to be
`
`equipment used commercially equipment used commercially
`
`in processing in processing
`
`these these
`
`Materials, Inc.’s direct control. THE SELLER MAKES NO Materials, Inc.’s direct control. THE SELLER MAKES NO
`
`reliable, but no reliable, but no
`
`representations, guarantees or representations, guarantees or
`
`materials, no warranties or guarantees are made as to materials, no warranties or guarantees are made as to
`
`WARRANTIES, EXPRESS OR IMPLIED, INCLUDING, WARRANTIES, EXPRESS OR IMPLIED, INCLUDING,
`
`warranties of any kind are made as to its accuracy, warranties of any kind are made as to its accuracy,
`
`the suitability of the suitability of
`
`the products the products
`
`
`for for
`the application the application
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`BUT NOT LIMITED TO, THE IMPLIED WARRANTIES BUT NOT LIMITED TO, THE IMPLIED WARRANTIES
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`suitability for particular applications or the results to be suitability for particular applications or the results to be
`
`disclosed. disclosed.
`
` Full-scale Full-scale
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`testing and end product testing and end product
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`OF MERCHANTABILITY AND FITNESS FOR A OF MERCHANTABILITY AND FITNESS FOR A
`
`obtained therefrom. The information is based on obtained therefrom. The information is based on
`
`performance are the responsibility of the user. Lubrizol performance are the responsibility of the user. Lubrizol
`
`PARTICULAR PURPOSE. Nothing contained herein is PARTICULAR PURPOSE. Nothing contained herein is
`
`laboratory work with small-scale equipment and does laboratory work with small-scale equipment and does
`
`Advanced Materials, Inc. shall not be liable for and the Advanced Materials, Inc. shall not be liable for and the
`
`to be considered as permission, recommendation, nor to be considered as permission, recommendation, nor
`
`not necessarily not necessarily
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`indicate end product performance. indicate end product performance.
`
`customer assumes all risk and liability of any use of customer assumes all risk and liability of any use of
`
`as an inducement to practice any patented invention as an inducement to practice any patented invention
`
`Because of the variations in methods, conditions and Because of the variations in methods, conditions and
`
`handling of any material beyond Lubrizol Advanced handling of any material beyond Lubrizol Advanced
`
`without permission of the patent owner. without permission of the patent owner.
`
`
`
`For further information, please visit www.pharma.lubrizol.comFor further information, please visit www.pharma.lubrizol.com
`Lubrizol Advanced Materials, Inc. is a wholly owned subsidiary of The Lubrizol Corporation
`
`* Trademark owned by The Lubrizol Corporation
`© Copyright 2011 / The Lubrizol Corporation
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`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 2 of 7
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`Benefits of Carbopol® Polymers, Pemulen™ Polymers and
`Noveon® Polycarbophil in Topical Formulations
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`
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`• Long history of safe and effective use in semi-solid formulations.
`
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`• Demonstrated to have low irritancy and non-sensitizing properties with repeated usage.
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`
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`• Compatibility with most acidic, basic, and neutral drugs.
`
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`• Applications across a broad pH range (4.5 - 10.0).
`
`
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`• Excellent thickening and suspending agents in aqueous, anhydrous and hydroalcoholic
`
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`systems. (Typical use levels in aqueous systems: 0.1 - 1.0% wt.)
`
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`• Consistent and reproducible properties due to their synthetic nature. Do not support
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`microbial growth.
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`• Chemically stable and maintain formulation stability.
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`• Excellent dispersions can be formed without alternate heating and cooling cycles.
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`• No heat sensitivity compared to other thickening agents.
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`
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`• Formulations can be sterilized by autoclaving or gamma radiation.
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`• Provide a non-greasy formulation, with no irritation.
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`
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`• Function as primary emulsifiers (Pemulen™ polymers) or emulsification stabilizers
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`(Carbopol® polymers).
`
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`• Possess shear thinning properties to facilitate extrusion from product packaging.
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`• Can increase bioavailability of the active pharmaceutical ingredient due to their
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`bioadhesive properties.
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`Selecting the Right Polymers for Semisolid Applications
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`Table 1 can be used for general guidance in selecting the appropriate polymer for semisolid formulations.
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`Numerous enhancements have been made to the Carbopol® polymer family over time to address
`regulatory requirements, meet formulation demands and improve product handling during processing. For
`example, the solvent system used to synthesize the polymers has evolved. Specifically, the “traditional”
`polymers are synthesized in benzene and the “toxicologically preferred” polymers are synthesized in either
`ethyl acetate or a cosolvent mixture of ethyl acetate and cyclohexane. Additionally, Carbopol® ETD and
`Ultrez polymers provide greater versatility in formulating and processing with their improved ease of
`dispersion.
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`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 3 of 7
`
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`Table 1
`Polymer Selection Guide for Semisolid Formulations
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`
`
`Product
`Residual
`Trade
`Solvent
`Name
`Carbopol® Polymers
`71G NF Ethyl
`Acetate
`
`971P NF Ethyl
`Acetate
`
`974P NF Ethyl
`Acetate
`
`980 NF Cosolvent
`
`981 NF Cosolvent
`
` 5984 EP Cosolvent
`
`ETD
`2020 NF Cosolvent
`
`Ultrez
`10 NF
`
`Cosolvent
`
`Application Type
`
`Lotions Creams Gels Bioadhesives
`
`Oral
`Liquids/Semisolids
`
`(cid:122)
`
`(cid:122)
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`(cid:122)
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`
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`
`
`
`
`(cid:122)
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`(cid:122)
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`
`
`(cid:122)
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`(cid:122)
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`(cid:122)
`
`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`Pharmacopeia Monograph
`Compendial Name
`Europe
`(Ph. Eur.)
`
`United
`States
`(USP/NF)
`
`Japan
`(JPE)1
`
`Carbomers* Carboxyvinyl
`Polymer
`
`Carbomers* Carboxyvinyl
`Polymer
`
`Carbomers* Carboxyvinyl
`Polymer
`
`Carbomers* Carboxyvinyl
`Polymer
`
`Carbomers* Carboxyvinyl
`Polymer
`
`Carbomers* Carboxyvinyl
`Polymer
`
`
`
`
`
`
`
`
`
`Carbomer
`Homopolymer
`Type A
`Carbomer
`Homopolymer
`Type A
`Carbomer
`Homopolymer
`Type B
`Carbomer
`Homopolymer
`Type C
`Carbomer
`Homopolymer
`Type A
`Carbomer
`Homopolymer
`Type B
`Carbomer
`Interpolymer
`Type B
`Carbomer
`Interpolymer
`Type A
`Carbomer
`934
`Carbomer
`934P
`Carbomer
`940
`Carbomer
`941
`Carbomer
`1342
`
`Carbomer
`Copolymer
`Type B
`Carbomer
`Copolymer
`Type A
`
`
`
`(cid:122)
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`(cid:122)
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`Polycarbophil
`
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`
`
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`
`
`Carboxyvinyl
`Polymer
`Carboxyvinyl
`Polymer
`Carboxyvinyl
`Polymer
`Carboxyvinyl
`Polymer
`
`
`
`
`
`
`
`
`(cid:122)
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`(cid:122)
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`(cid:122)
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`
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
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`(cid:122)
`
`(cid:122)
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`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
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`* The Carbomers Monograph in the European Pharmacopeia stipulates that benzene is limited to 2 ppm.
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`
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`1 Based on customer request, Lubrizol certifies select lots of product against the JPE Carboxyvinyl Polymer Monograph
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`934 NF
`
`Benzene
`
`934P NF Benzene
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`940 NF
`
`Benzene
`
`941 NF
`
`Benzene
`
`1342 NF Benzene
`Pemulen™ Polymers
`
`TR-1 NF Cosolvent
`
`TR-2 NF Cosolvent
`
`(cid:122)
`
`(cid:122)
`
`
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`Noveon® Polycarbophil USP
`AA-1
`Ethyl
`
`USP
`Acetate
`
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`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 4 of 7
`
`
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`Table 2
`Carbopol® Polymer Recommended Substitutes
`
`The following table shows recommended substitutes for the benzene grade Carbopol® products based on
`viscosity criteria. The substitute products are polymerized in either ethyl acetate or a cosolvent mixture of
`ethyl acetate and cyclohexane. If a substitution is made in a pharmaceutical formulation, it is recommended
`that key performance properties be ascertained and regulatory considerations be taken into account.
`Depending on the desired dosage requirements, other Carbopol® polymers may be suitable alternatives.
`
`Recommended Non-Benzene Carbopol® or
`Benzene Grade
`Carbopol® Polymers
`Pemulen™ Polymers
`Carbopol® 934 NF polymer
`Carbopol® 5984 EP and Ultrez 10 NF polymers
`Carbopol® 934P NF polymer Carbopol® 974P NF polymer
`Carbopol® 940 NF polymer
`Carbopol® 980 NF and Ultrez 10 NF polymer
`Carbopol® 941 NF polymer
`Carbopol® 71G NF, 971P NF and 981 NF polymers
`Carbopol® 1342 NF polymer
`Pemulen™ TR-1 NF and TR-2 polymers
`Formulating Topical Gels
`
`Carbopol® polymers, Pemulen™ polymers and Noveon® polycarbophil are highly efficient thickeners,
`suspending aids, and emulsifying agents for topical formulations and oral liquids/semisolids. A key benefit
`of the polymers is their high efficiency at low usage levels (0.1 - 3 wt.%).
`
`Carbopol® polymers can be used as rheology modifiers in anhydrous systems with or without
`neutralization. For more details, see Pharmaceutical Bulletin 5: “Neutralization Procedures”.
`
`Carbopol® Ultrez 10 NF polymer provides excellent versatility in processing for topical formulations. Its
`unique dispersion performance allows it to wet quickly, yet hydrate slowly. This minimizes agglomeration,
`which can be a problem if turbulent mixing is not available during dispersion. Compared with traditional
`Carbopol® polymers, Carbopol® Ultrez 10 NF polymer provides dispersions in water that are much lower in
`viscosity prior to neutralization which enables easier handling in mixing tanks and process lines. Once the
`polymer is neutralized, it is a highly efficient thickener.
`
`Formulating Topical Gels
`Typical usage levels of Carbopol® polymers in topical aqueous or hydroalcoholic gels is 0.5% - 3 wt. %.
`General recommendations for formulation and processing appear below.
`1. Choice of Neutralizer — Upon neutralization, Carbopol® polymer should form a salt that is swellable
`in the vehicle.
`
`2. pH — The optimum pH range for a Carbopol® polymer is 4 - 10.
`
`3. Complexation with Other
`Ingredients — Proteins, povidone, polyethylene glycol and
`polyethoxylated surfactants might form a complex with unneutralized Carbopol® polymers. In order to
`prevent the complexation, these ingredients should be added to the partially neutralized dispersion.
`
`4. Electrolytes, Metals — Carbopol® polymers are sensitive to electrolytes, and preferably their level
`should be minimized. It is recommended to use the non ionized form of the API whenever possible. An
`increased level of Carbopol® polymer may be used to compensate for the effect of electrolytes on
`viscosity. Alternatively, a more salt tolerant grade of the polymer may be used such as Carbopol®