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` PHARMACEUTICAL BULLETIN
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`Pharmaceutical Bulletin 21
`Edition: October 29, 2008
`Previous Edition: August 15, 2005
`
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`FFoorrmmuullaattiinngg SSeemmiissoolliidd PPrroodduuccttss
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`Carbopol®* polymers, Pemulen™* polymers and Noveon®* polycarbophils 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® polycarbophils, 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
`
`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
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`these these
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`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
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`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
`
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`for for
`the application the application
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`suitability for particular applications or the results to be suitability for particular applications or the results to be
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`OF MERCHANTABILITY AND FITNESS FOR A OF MERCHANTABILITY AND FITNESS FOR A
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`disclosed. disclosed.
`
` Full-scale Full-scale
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`testing and end product testing and end product
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`obtained therefrom. The information is based on obtained therefrom. The information is based on
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`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
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`Advanced Materials, Inc. shall not be liable for and the Advanced Materials, Inc. shall not be liable for and the
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`not necessarily not necessarily
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`indicate end product performance. indicate end product performance.
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`as an inducement to practice any patented invention as an inducement to practice any patented invention
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`customer assumes all risk and liability of any use of customer assumes all risk and liability of any use of
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`Because of the variations in methods, conditions and Because of the variations in methods, conditions and
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`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 2008 / The Lubrizol Corporation
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`1
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`AMN1021
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`

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`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 2 of 7
`
`Benefits of Carbopol® Polymers, Pemulen™ Polymers and
`Noveon® Polycarbophils 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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`
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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.
`
`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.
`
`2
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`

`

`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 3 of 7
`
`
`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
`
`Cosolvent
`
`Application Type
`
`Lotions Creams Gels Bioadhesives
`
`Oral
`Liquids/Semisolids
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`
`
`
`
`(cid:122)
`
`(cid:122)
`
`
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`
`
`
`
`
`
`
`
`
`
`Pharmacopeia Monograph
`Compendial Name
`Europe
`(Ph. Eur.)
`
`United
`States
`(USP/NF)
`
`Japan
`(JPE)
`
`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)
`
`
`
`
`
`
`
`
`
`
`
`(cid:122)
`
`Polycarbophil
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Carboxyvinyl
`Polymer
`Carboxyvinyl
`Polymer
`Carboxyvinyl
`Polymer
`Carboxyvinyl
`Polymer
`
`
`
`
`
`
`
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`(cid:122)
`
`
`* The Carbomers Monograph in the European Pharmacopeia stipulates that benzene is limited to 2 ppm.
`
`
`
`
`Ultrez
`10 NF
`
`934 NF
`
`Benzene
`
`934P NF Benzene
`
`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
`
`3
`
`

`

`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 4 of 7
`
`
`
`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® ETD
`2020 NF, Pemulen™ TR-1 NF or Pemulen™ TR-2 NF polymers. Additionally, deionized or distilled water
`should be used. Salts should be added after neutralization of the dispersion in order to reduce their
`impact on product viscosity. Multivalent cations (Ca2+, Mg2+, Fe3+, Al3+, etc.) should not be used with
`Carbopol® polymers.
`
`
`
`
`
`4
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`

`

`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 5 of 7
`
`
`Contamination with transition metals (Fe, Cu, etc.) causes a gradual reduction in viscosity. It is
`recommended to include EDTA in the formulation as a complexing agent. Processing in stainless
`steel or nonmetallic equipment will minimize the effect of metals.
`
`5. Dispersion Techniques — Like many fine powders, traditional Carbopol® polymers, as well as
`Pemulen™ polymers and Noveon® polycarbophils, tend to agglomerate when improperly added to the
`solvent. Therefore, proper dispersion techniques must be followed to prevent excessively long mixing
`cycles, reduced viscosity and dispersion defects such as grainy texture, fluctuations in pH and
`viscosity and the formation of insoluble particles resembling “fish eyes.” If improper dispersion
`techniques are utilized, the surface of the agglomerated particles solvates to form a tough outer layer
`which prevents complete wetting of the interior polymer particles.
`
`Carbopol® polymers can be dispersed by sifting the polymer into water, using an eductor or
`mechanical in-line powder disperser. For more details, see Pharmaceutical Bulletin 4: “Dispersion
`Techniques for Lubrizol Pharmaceutical Polymers”.
`
`into Carbopol® Polymer Dispersions -
`Ingredients
`6. Incorporating Active Pharmaceutical
`Carbopol® polymers, Pemulen™ polymers and Noveon® polycarbophils dispersions can be used as
`the vehicle in liquid and semisolid dosage forms. Other pharmaceutical ingredients are incorporated
`into the formulation via two different methods depending on the physical/chemical properties.
`
`Insoluble Ingredients
`Insoluble ingredients can be incorporated into the polymeric dispersion either before or after it is
`neutralized.
`
`Soluble Ingredients
`Soluble ingredients can be dissolved in the water used to make the polymeric dispersion. Some
`soluble ingredients are added to the final formulation to avoid compatibility issues (for example,
`electrolytes are added at the end).
`
`7. High Shear Mixing or Pumping — Carbopol® polymers thicken by forming a gel matrix. High shear
`mixing, with colloid mills, homogenizers, etc., or high shear pumping can break down the polymer structure
`resulting in viscosity loss. If necessary, an in-line homogenizer can be used to minimize the
`homogenization time. Low shear pumps, such as reciprocating diaphragm or auger/gear pumps should be
`used.
`
`Transparent Hydroalcoholic Gels
`
`Ethanol or other alcohols (propylene glycol, isopropanol) can be used in hydroalcoholic gels to dissolve
`low solubility active pharmaceutical
`ingredients
`instead of using solubilizers such as PEG-40
`hydrogenated castor oil, polysorbate 20, etc. The absence of a solubilizer greatly improves the aesthetics
`of the product as the stickiness and “rubbery” feel is virtually absent. Due to the large ethanol content,
`additional preservatives may not be required.
`
`The viscosity of an aqueous gel is usually higher than the viscosity of a hydroalcoholic gel due to more
`hydrogen bonding. Viscosity of the hydroalcoholic gel can be adjusted by increasing the level of
`Carbopol® polymer.
`
`To manufacture transparent hydroalcoholic gels based on Carbopol® polymer, the ethanolic solution
`should be added to the hydrogel (Carbopol polymer pre-dispersed in water) using a slowly moving anchor
`mixer. Also, to reduce air entrapment in the final product, the ethanol solution should be degassed prior to
`addition as the solubility of air in ethanol is quite high. Degassing of the alcoholic solution is best done by
`filtering through a glass filter under reduced pressure.
`
`Neutralization of hydroalcoholic gels with Carbopol® polymer can be accomplished using different bases.
`The amine salt of Carbopol® polymer must be swellable in the solvent system. If it is not, it will precipitate
`
`5
`
`

`

`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 6 of 7
`
`
`
`and no thickening will occur. Triethanolamine can be used in hydroalcoholic gels with up to 50% alcohol.
`A higher alcohol level requires more alcohol soluble amines, such as tetrahydroxypropyl ethylenediamine,
`PEG 15 Cocamine, diisopropylamine, amino methyl propanol or tromethamine. For more details, see
`Pharmaceutical TDS 237: “Neutralizing Carbopol and Pemulen Polymers in Aqueous and Hydroalcoholic
`Systems”
`
`Formulating Creams and Lotions
`Carbopol® polymers can be used to stabilize creams and lotions. In contrast, Pemulen™ polymers can
`both stabilize and emulsify (function as primary emulsifiers) oil-in-water emulsions. These emulsifiers
`have a small lipophilic portion in addition to a large hydrophilic portion. The lipophilic portion adsorbs at
`the oil-water interface, and the hydrophilic portion swells in the water forming a gel network around oil
`droplets to provide exceptional emulsion stability to a broad range of oils.
`
`See Pharmaceutical Bulletin 8: “Emulsification Properties” for more information on using Pemulen™
`polymers to emulsify your topical creams or lotions.
`
`Formulating Topical Emulsions
`
`Typical usage levels of Pemulen™ polymers in topical emulsions is 0.1% - 0.4 wt.%. As described in
`Bulletin 8: “Emulsification Properties”, more Pemulen™ polymer is not necessarily better. The viscosity of
`the external phase can be increased by using Carbopol® polymer in addition to Pemulen™ polymer.
`General recommendations for formulation and processing appear below.
`
`1. pH — The optimum pH range for an emulsion using Pemulen™ polymeric emulsifiers is 4-8. A pH above
`or below this range may cause an unstable emulsion.
`
`2. High Shear Mixing or Pumping — Pemulen™ polymers stabilize the emulsion by forming a gel around
`the oil droplet. High shear mixing, with colloid mills, homogenizers, etc., or high shear pumping can break
`down the polymer structure resulting in viscosity loss and emulsion instability. If necessary, an in-line
`homogenizer can be used to minimize the homogenization time. Low shear pumps, such as reciprocating
`diaphragm or auger/gear pumps should be used.
`
`3. Electrolytes, Metals — Pemulen™ 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.
`Additionally, deionized or distilled water should be used. Salts should be added after neutralization of
`the dispersion in order to reduce their impact on product viscosity. Multivalent cations (Ca2+, Mg2+,
`Fe3+, Al3+, etc.) should not be used with Pemulen™ polymers because they will break the emulsion.
`Contamination with transition metals (Fe, Cu, etc.) causes a gradual reduction in viscosity and
`emulsion instability. It is recommended to include EDTA in the formulation as a complexing agent.
`Processing in stainless steel or nonmetallic equipment will minimize the effect of metals.
`
`4. Droplet Size — Pemulen™ polymers can produce extremely stable macro emulsions, even at large
`average oil droplet sizes (approaching 1 - 2 millimeters diameter). For aesthetic reasons, it is often
`desirable to produce small particle size emulsions having a high degree of whiteness, opacity and
`creamy appearance. The droplet size of the oil phase can be reduced by increasing the mixing time,
`using moderate shear agitation when the emulsion is made, or by the use of a liquid nonionic
`surfactant (HLB 8-12) at 0.1 - 0.4 wt. %.
`
`5. Emulsification Method — Both a direct and indirect method could be used to create an emulsion with
`Pemulen™ polymers.
`
`
`
`
`
`6
`
`

`

`PHARMACEUTICAL BULLETIN 21
`FORMULATING TOPICAL PRODUCTS
`Page 7 of 7
`
`References
`
`Al-Khamis, K. I., Davis, S. S., Hadcraft, J., 1986. Microviscosity and Drug Release from Topical Gel
`Formulations. Pharm. Res. 3(4), 214-217.
`
`Allingham, R., Williams, P., Crouch Jr., E., Loewy, D., Demkowski, H., 1988. Topically Applied
`Aminocaproic Acid Concentrates in the Aqueous Humor of the Rabbit in Therapeutic Levels. Arch.
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`
`Amin, P, Fruitwala, M., 1994. Erythromycin Gel – A Topical Anti Acne Preparation. Drug Dev. Ind. Pharm.
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`
`A-sasutjarit, R., Sirivat, A., Vayumhasuwan, P., 2005. Viscoelastic Properties of Carbopol 940 Gels and
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`
`Bremecker, K., Koch, B., Krause, W., Neuenroth, L., 1992. Application-Triggered Drug Release From an Oil-
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`
`DiColo, G., Carelli, V., Giannaccini, B., Serafini, M.F., Bottari, F., 1980. Vehicle Effects in Percutaneous
`Absorption: In Vitro Study of Influence of Solvent Powder and Microscopic Viscosity of Vehicle on
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`
`Duckova, K., Kucera, J., 1990. Formulation of Topical Preparations for Local Treatment of Burns. Acta
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`
`Fiorilli, A., Molteni, B., Milani, M., 2005. Successful treatment of bacterial vaginosis with a polycarbophil-
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`Obstet. Gynecol. Reprod. Biol. 120(2), 202-205.
`
`Jimenez, M., Fresno, M., Ramirez, A., 2005. The influence of cosolvent polarity on the flow properties of
`hydroalcoholic gels. Empirical models. Chem. Pharm. Bull., 53(9), 1097-1102.
`
`Leibowitz, H., Chang, R., Mandell, A., 1984. Gel Tears: A New Medication for the Treatment of Dry Eyes.
`Ophthalmology. 91(10), 1199-12204.
`
`Li, L., Mathias, N., Heran, C., Moench, P., Wall, D., Smith, R., 2005. Carbopol-mediated paracellular
`transport enhancement in Calu-3 cell layers. J. Pharm. Sci., 95(2), 326-335.
`
`Mutalik, Sr., Udupa, N., 2005. Formulation development, in vitro and in vivo evaluation of membrane
`controlled transdermal systems of glibenclamide. J. Pharm. Pharmaceut. Sci. 8(1), 26-38.
`
`Nagai, T., 1985. Adhesive Topical Drug Delivery System. J. Control. Rel. 2. 121-34.
`
`Oppong, F., Rubatat, L., Frisken, B., Bailey, A., de Bruyn, J., 2006. Microrheology and structure of a yield-
`stress polymer gel. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 73(4-1), 041405/1-041405/9.
`
`Ruiz, M.A., Gallardo, V., Delgado, A., Vera, P., 1994. Study of In-Vitro Release of Corticoids in Topicals
`Formulations. Il Farmaco, 49(2), 147-52.
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