Name: Carbomer
CAS No: Carbomer [9003-01-4], 934 ([9007-16-3]), 940 ([9007-17-4]), 941 ([9062-04-08]), [9007-20-9]
BP: Carbomers PhEur: Carbomers USP-NF: Carbomer Note that the USP32–NF27 contains several individual carbomer monographs; see Sections 4 and 9.
Acrypol; Acritamer; acrylic acid polymer; carbomera; Carbopol; carboxy polymethylene; polyacrylic acid; carboxyvinyl polymer; Pemulen; Tego Carbomer.
Carbomer [9003-01-4], 934 ([9007-16-3]), 940 ([9007-17-4]), 941 ([9062-04-08]), [9007-20-9]
Carbomers are synthetic high-molecular-weight polymers of acrylic acid that are crosslinked with either allyl sucrose or allyl ethers of pentaerythritol. They contain between 52% and 68% of carboxylic acid (COOH) groups calculated on the dry basis. The BP 2009 and PhEur 6.4 have a single monograph describing carbomer; the USP32–NF27 contains several monographs describing individual carbomer grades that vary in aqueous viscosity, polymer type, and polymerization solvent. The molecular weight of carbomer is theoretically estimated at 7 105 to 4 109 . In an effort to measure the molecular weight between crosslinks, MC, researchers have extended the network theory of elasticity to swollen gels and have utilized the inverse relationship between the elastic modulus and MC. (1–3) Estimated MC values of 237 600 g/mol for Carbopol 941 and of 104 400 g/mol for Carbopol 940 have been reported.(4) In general, carbomer polymers with lower viscosity and lower rigidity will have higher MC values. Conversely, higher-viscosity, more rigid carbomer polymers will have lower MC values.
Carbomer polymers are formed from repeating units of acrylic acid. The monomer unit is shown above. The polymer chains are crosslinked with allyl sucrose or allyl pentaerythritol. See also Section 4.
Carbomers are used in liquid or semisolid pharmaceutical formulations as rheology modifiers. Formulations include creams, gels, lotions and ointments for use in ophthalmic,(5–7) rectal,(8–10) topical(11–20) and vaginal(21,22) preparations. Carbomer grades with residual benzene content greater than 2 ppm do not meet the specifications of the PhEur 6.4 monograph. However, carbomer having low residuals of other solvents than the ICH-defined ‘Class I OVI solvents’ may be used in Europe. Carbomer having low residuals of ethyl acetate, such as Carbopol 971P NF or Carbopol 974P NF, may be used in oral preparations, in suspensions, capsules or tablets.(23–35) In tablet formulations, carbomers are used as controlled release agents and/or as binders. In contrast to linear polymers, higher viscosity does not result in slower drug release with carbomers. Lightly crosslinked carbomers (lower viscosity) are generally more efficient in controlling drug release than highly crosslinked carbomers (higher viscosity). In wet granulation processes, water, solvents or their mixtures can be used as the granulating fluid. The tackiness of the wet mass may be reduced by including talc in the formulation or by adding certain cationic species to the granulating fluid.(36) However, the presence of cationic salts may accelerate drug release rates and reduce bioadhesive properties. Carbomer polymers have also been investigated in the preparation of sustained-release matrix beads,(26–39) as enzyme inhibitors of intestinal proteases in peptide-containing dosage forms,(40–42) as a bioadhesive for a cervical patch(43) and for intranasally administered microspheres,(44) in magnetic granules for site-specific drug delivery to the esophagus,(45) and in oral mucoadhesive controlled drug delivery systems.(46–49) Carbomers copolymers are also employed as emulsifying agents in the preparation of oil-in-water emulsions for external administration. Carbomer 951 has been investigated as a viscosity-increasing aid in the preparation of multiple emulsion microspheres.(50) Carbomers are also used in cosmetics. Therapeutically, carbomer formulations have proved efficacious in improving symptoms of moderate-to-severe dry eye syndrome.(51,52) See Table I.
Carbomers are white-colored, ‘fluffy’, acidic, hygroscopic powders with a characteristic slight odor. A granular carbomer is also available (Carbopol 71G).
The USP32–NF27 has several monographs for different carbomer grades, while the BP 2009 and PhEur 6.4 have only a single monograph. The USP32–NF27 lists three umbrella monographs, carbomer copolymer, carbomer homopolymer and carbomer interpolymer, which separate carbomer products based on polymer structure and apply to products not polymerized in benzene. The differentation within each umbrella monograph is based on viscosity characteristics (Type A, Type B and Type C). The USP32–NF27 also lists monographs for carbomer 934, 934P, 940 and 941, which are manufactured using benzene. Currently these monographs can apply to products manufactured both with and without the use of benzene. Effective from January 1 2011, products manufactured without the use of benzene will be officially titled Carbomer Homopolymer provided they comply with the carbomer homopolymer monograph. The USP32–NF27 also includes carbomer 1342, which applies to carbomer copolymers manufactured using benzene. Carbomer polymers are also covered either individually or together in other pharmacopeias. See Table II. See also Section 18. Note that unless otherwise indicated, the test limits shown above apply to all grades of carbomer.
Acidity/alkalinity pH = 2.5–4.0 for a 0.2% w/v aqueous dispersion; pH = 2.5–3.0 for Acrypol 1% w/v aqueous dispersion. Density (bulk) 0.2 g/cm3 (powder); 0.4 g/cm3 (granular). Density (tapped) 0.3 g/cm3 (powder); 0.4 g/cm3 (granular). Dissociation constant pKa = 6.00.5 Glass transition temperature 100–1058C Melting point Decomposition occurs within 30 minutes at 2608C. See Section 11. Moisture content Typical water content is up to 2% w/w. However, carbomers are hygroscopic and a typical equilibrium moisture content at 258C and 50% relative humidity is 8–10% w/w. The moisture content of a carbomer does not affect its thickening efficiency, but an increase in the moisture content makes the carbomer more difficult to handle because it is less readily dispersed. NIR spectra see Figure 1. Particle size distribution Primary particles average about 0.2 mm in diameter. The flocculated powder particles average 2–7 mm in diameter and cannot be broken down into the primary particles.A granular carbomer has a particle size in the range 150–425 mm. Solubility Swellable in water and glycerin and, after neutralization, in ethanol (95%). Carbomers do not dissolve but merely swell to a remarkable extent, since they are three-dimensionally crosslinked microgels. Specific gravity 1.41 Viscosity (dynamic) Carbomers disperse in water to form acidic colloidal dispersions that, when neutralized, produce highly viscous gels. Carbomer powders should first be dispersed into vigorously stirred water, taking care to avoid the formation of indispersible agglomerates, then neutralized by the addition of a base. The Carbopol ETD and Ultrez series of carbomers were introduced to overcome some of the problems of dispersing the powder into aqueous solvents. These carbomers wet quickly yet hydrate slowly, while possessing a lower unneutralized dispersion viscosity. Agents that may be used to neutralize carbomer polymers include amino acids, potassium hydroxide, sodium bicarbonate, sodium hydroxide, and organic amines such as triethanolamine. One gram of carbomer is neutralized by approximately 0.4 g of sodium hydroxide. During preparation of the gel, the solution should be agitated slowly with a broad, paddlelike stirrer to avoid introducing air bubbles. Neutralized aqueous gels are more viscous at pH 6–11. The viscosity is considerably reduced at pH values less than 3 or greater than 12, or in the presence of strong electrolytes.(36,53) Gels rapidly lose viscosity on exposure to ultraviolet light, but this can be minimized by the addition of a suitable antioxidant. See also Section 11.
Carbomers are stable, hygroscopic materials that may be heated at temperatures below 1048C for up to 2 hours without affecting their thickening efficiency. However, exposure to excessive temperatures can result in discoloration and reduced stability. Complete decomposition occurs with heating for 30 minutes at 2608C. Dry powder forms of carbomer do not support the growth of molds and fungi. In contrast, microorganisms grow well in unpreserved aqueous dispersions, and therefore an antimicrobial preservative such as 0.1% w/v chlorocresol, 0.18% w/v methylparaben–0.02% w/v propylparaben, or 0.1% w/v thimerosal should be added. The addition of certain antimicrobials, such as benzalkonium chloride or sodium benzoate, in high concentrations (0.1% w/v) can cause cloudiness and a reduction in viscosity of carbomer dispersions. Aqueous gels may be sterilized by autoclaving(7) with minimal changes in viscosity or pH, provided care is taken to exclude oxygen from the system, or by gamma irradiation, although this technique may increase the viscosity of the formulation.(54,55) At room temperature, carbomer dispersions maintain their viscosity during storage for prolonged periods. Similarly, dispersion viscosity is maintained, or only slightly reduced, at elevated storage temperatures if an antioxidant is included in the formulation or if the dispersion is stored protected from light. Exposure to light causes oxidation that is reflected in a decrease in dispersion viscosity. Stability to light may be improved by the addition of 0.05–0.1% w/v of a water-soluble UV absorber such as benzophenone-2 or benzophenone-4 in combination with 0.05–0.1% w/v edetic acid. Carbomer powder should be stored in an airtight, corrosionresistant container and protected from moisture. The use of glass, plastic, or resin-lined containers is recommended for the storage of formulations containing carbomer.
Carbomers are discolored by resorcinol and are incompatible with phenol, cationic polymers, strong acids, and high levels of electrolytes. Certain antimicrobial adjuvants should also be avoided or used at low levels, see Section 11. Trace levels of iron and other transition metals can catalytically degrade carbomer dispersions. Certain amino-functional actives form complexes with carbomer; often this can be prevented by adjusting the pH of the dispersion and/or the solubility parameter by using appropriate alcohols and polyols. Carbomers also form pH-dependent complexes with certain polymeric excipients. Adjustment of pH and/or solubility parameter can also work in this situation.
Carbomers are synthetic, high-molecular-weight, crosslinked polymers of acrylic acid. These acrylic acid polymers are crosslinked with allyl sucrose or allyl pentaerythritol. The polymerization solvent used previously was benzene; however, some of the newer commercially available grades of carbomer are manufactured using either ethyl acetate or a cyclohexane–ethyl acetate cosolvent mixture. The Carbopol ETD and Carbopol Ultrez polymers are produced in the cosolvent mixture with a proprietary polymerization aid.
Carbomers are used extensively in nonparenteral products, particularly topical liquid and semisolid preparations. Grades polymerized in ethyl acetate may also be used in oral formulations; see Section 18. There is no evidence of systemic absorption of carbomer polymers following oral administration.(56) Acute oral toxicity studies in animals indicate that carbomer 934P has a low oral toxicity, with doses up to 8 g/kg being administered to dogs without fatalities occurring. Carbomers are generally regarded as essentially nontoxic and nonirritant materials;(57) there is no evidence in humans of hypersensitivity reactions to carbomers used topically. LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934(58) LD50 (guinea pig, oral): 2.5 g/kg for carbomer 934P LD50 (guinea pig, oral): 2.5 g/kg for carbomer 940 LD50 (mouse, IP): 0.04 g/kg for carbomer 934P LD50 (mouse, IP): 0.04 g/kg for carbomer 940 LD50 (mouse, IV): 0.07 g/kg for carbomer 934P LD50 (mouse, IV): 0.07 g/kg for carbomer 940 LD50 (mouse, oral): 4.6 g/kg for carbomer 934P LD50 (mouse, oral): 4.6 g/kg for carbomer 934 LD50 (mouse, oral): 4.6 g/kg for carbomer 940 LD50 (rat, oral): 10.25 g/kg for carbomer 910 LD50 (rat, oral): 2.5 g/kg for carbomer 934P LD50 (rat, oral): 4.1 g/kg for carbomer 934 LD50 (rat, oral): 2.5 g/kg for carbomer 940 LD50 (rat, oral): > 1g/kg for carbomer 941 No observed adverse effect level (NOAEL) (rat, dog, oral): 1.5 g/kg for carbomer homopolymer type B.(59)
Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive dust generation should be minimized to avoid the risk of explosion (lowest explosive concentration is 130 g/m3 ). Carbomer dust is irritating to the eyes, mucous membranes, and respiratory tract. In the event of eye contact with carbomer dust, saline should be used for irrigation purposes. Gloves, eye protection, and a dust respirator are recommended during handling. A solution of electrolytes (sodium chloride) is recommended for cleaning equipment after processing carbomers.
Included in the FDA Inactive Ingredients Database (oral suspensions, tablets; ophthalmic, rectal, topical, transdermal preparations; vaginal suppositories). Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Nonmedicinal Ingredients.
Polycarbophil.
A specification for carbomer is contained in the Japanese Pharmaceutical Excipients (JPE).(60) A number of different carbomer grades are commercially available that vary in their chemical structure, degree of crosslinking, and residual components. These differences account for the specific rheological, handling, and use characteristics of each grade. Carbomer grades that have the polymer backbone modified with long-chain alkyl acrylates are used as polymeric emulsifiers or in formulations requiring increased resistance to ions. Polycarbophils, poly(acrylic acid) polymers crosslinked with divinyl glycol, are available for bioadhesive or medicinal applications. In general, carbomers designated with the letter ‘P’, e.g. Carbopol 971P, are the pharmaceutical grade polymers for oral or mucosal contact products. Carbomer copolymer (or homopolymer or interpolymer) obtained from different manufacturers or produced in different solvents with different manufacturing processes may not have identical properties with respect to its use for specific pharmaceutical purposes, e.g. as tablet controlled release agents, bioadhesives, topical gellants, etc. Therefore, types of carbomer copolymer (or homopolymer or interpolymer) should not be interchanged unless performance equivalency has been ascertained.