med 10

Polyethylene glycols are widely used in a variety of pharma- ceutical formulations. Generally, they are regarded as nontoxic and nonirritant materials.(17–19)

Adverse reactions to polyethylene glycols have been reported, the greatest toxicity being with glycols of low molecular weight. However, the toxicity of glycols is relatively low.

Polyethylene glycols administered topically may cause stinging, especially when applied to mucous membranes. Hypersensitivity reactions to polyethylene glycols applied topically have also been reported, including urticaria and delayed allergic reactions.(20)

The most serious adverse effects associated with polyethy- lene glycols are hyperosmolarity, metabolic acidosis, and renal failure following the topical use of polyethylene glycols in burn patients.(21) Topical preparations containing polyethylene glycols should therefore be used cautiously in patients with renal failure, extensive burns, or open wounds.

Table IV: Specifications from PhEur 2005.

Type of PEG Density (g/cm3) Freezing point (8C) Hydroxyl value Viscosity (dynamic) [mPa s (cP)] Viscosity (kinematic) [mm2/s (cSt)]

300 1.120 — 340–394 80–105 71–94

400 1.120 — 264–300 105–130 94–116

600 1.080 15–25 178–197 15–20 13.9–18.5

1000 1.080 35–40 107–118 22–30 20.4–27.7

1500 1.080 42–48 70–80 34–50 31–46

3000 1.080 50–56 34–42 75–100 69–93

3350 1.080 53–57 30–38 83–120 76–110

4000 1.080 53–59 25–32 110–170 102–158

6000 1.080 55–61 16–22 200–270 185–250

8000 1.080 55–62 12–16 260–510 240–472

20000 1.080 557 — 2 700–3 500 2 500–3 200

35000 1.080 557 — 11 000–14 000 10 000–13 000

548 Polyethylene Glycol

Figure 1: Equilibrium moisture content of PEG 4000 (McKesson, Lot No. B192–8209) at 258C.

Figure 3: Equilibrium moisture content of PEG 6000 at 258C.

⃝: PEG 6000 powder (Union Carbide Corp., Lot no. B–507)

Q: PEG E–6000 (BASF, Lot no. WPNA–124B)

Figure 2: Equilibrium moisture content of PEG 4000 at 258C.

⃝: PEG 4000 powder (Union Carbide Corp, Lot no. B- 251)

Q: PEG E–4000 (BASF, Lot no. WPYA–575B)

Figure 4: Particle size distribution of PEG 4000 and PEG 6000 flakes.

⃝: PEG 4000 flakes

Q: PEG 6000 flakes

Polyethylene Glycol 549

Table V: Specification for viscosity of polyethylene glycol of the given nominal molecular weight at 98.98C 0.38C from the USPNF 23.

Type of PEG (nominal average molecular weight)

Viscosity (kinematic) [mm2/s (cSt)]

Figure 5: Particle size distribution of PEG 4000 and PEG 6000 powder.

⃝: PEG 4000 powder

Q: PEG 6000 powder

Oral administration of large quantities of polyethylene glycols can have a laxative effect. Therapeutically, up to 4 L of an aqueous mixture of electrolytes and high-molecular-weight polyethylene glycol is consumed by patients undergoing bowel cleansing.(22)

Liquid polyethylene glycols may be absorbed when taken orally, but the higher-molecular-weight polyethylene glycols are not significantly absorbed from the gastrointestinal tract. Absorbed polyethylene glycol is excreted largely unchanged in the urine, although polyethylene glycols of low molecular weight may be partially metabolized.

For animal toxicity data, see Table VII.(24)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection is recom- mended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (dental preparations; IM and IV injections; ophthalmic preparations; oral capsules, solutions, syrups, and tablets; rectal, topical, and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

7500 405–735

8000 470–900

Table VI: Viscosity of selected polyethylene glycols at 258C and 998C.

Type of PEG Viscosity [mm2/s (cSt)] 258C 998C

PEG 1000 solid 19.5 —

PEG 2000 solid 47 —

PEG 4000 solid 180 —

PEG 6000 solid 580 —

PEG 20000 solid 6 900 —

550 Polyethylene Glycol

Table VII: Animal toxicity data (LD50) for various grades of polyethylene glycol.(24)

PEG grade LD50 (g/kg)

Guinea pig (oral) Mouse (IP) Mouse (IV) Mouse (oral) Rabbit (oral) Rabbit (IV) Rat (IP) Rat (IV) Rat (oral)

PEG 200 — 7.5 — 34 19.9 — — — 28.0

PEG 300 19.6 — — — 17.3 — — — 27.5

PEG 400 15.7 10.0 8.6 28.9 26.8 — 9.7 7.3 —

PEG 600 — — — 47 — — — — 38.1

PEG 1000 — 20 — — — — 15.6 — 32

PEG 1500 28.9 — — — 28.9 8 17.7 — 44.2

PEG 4000 50.9 — 16 — 76 — 11.6 — 50

PEG 6000 50 — — — — — 6.8 — —

Related Substances

Polyoxyethylene alkyl ethers; polyethylene oxide; polyoxyethy- lene sorbitan fatty acid esters; polyoxyethylene stearates; suppository bases.

Comments

A specification for polyethylene glycol is contained in the Food Chemicals Codex (FCC).

Specific References

Mohl S, Winter G. Continuous release of rh-interferon alpha-2a from triglyceride matrices. J Control Release 2004; 97(1): 67–78.

Hadia IA, Ugrine´ HE, Farouk AM, Shayoub M. Formulation of polyethylene glycol ointment bases suitable for tropical and subtropical climates I. Acta Pharm Hung 1989; 59: 137–142.

Kellaway IW, Marriott C. Correlations between physical and drug release characteristics of polyethylene glycol suppositories. J Pharm Sci 1975; 64: 1162–1166.

Wells JI, Bhatt DA, Khan KA. Improved wet massed tableting using plasticized binder. J Pharm Pharmacol 1982; 34 (Suppl.): 46P.

Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci 1971; 60: 1281–1302.

Ford JL, Rubinstein MH. Formulation and ageing of tablets prepared from indomethacin–polyethylene glycol 6000 solid dispersions. Pharm Acta Helv 1980; 55: 1–7.

Vila-Jato JL, Blanco J, Alonso MJ. The effect of the molecular weight of polyethylene glycol on the bioavailability of paraceta- mol–polyethylene glycol solid dispersions. J Pharm Pharmacol 1986; 38: 126–128.

Miralles MJ, McGinity JW, Martin A. Combined water-soluble carriers for coprecipitates of tolbutamide. J Pharm Sci 1982; 71: 302–304.

Okhamafe AO, York P. Moisture permeation mechanism of some aqueous-based film coats. J Pharm Pharmacol 1982; 34 (Suppl.): 53P.

Marishita M, Goto T, Peppas NA, et al. Mucosal insulin delivery systems based on complexation polymer hydrogels: effect of particle size on insulin enteral absorption. J Control Release 2004; 97(1): 67–78.

Marcel T, Nagappan P, Nerenbaum L, et al. Calcium phosphate- PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin. Int J Pharm 2004; 277(1–2): 91–97.

Fiegel J, Fu H, Hanes J. Poly(ether-anhydride) dry powder aerosols for sustained drug delivery in the lungs. J Control Release 2004; 96(3): 411–423.

Jaiswal J, Gupta SK, Kreuter J. Preparation of biodegradable cyclosporine nanoparticles by high-pressure emulsion-solvent evaporation process. J Control Release 2004; 96(1): 169–178.

Jung SW, Jeong YI, Kim YH, Kim SH. Self-assembled polymeric nanoparticles of poly(ethylene glycol) grafted pullulan acetate as a novel drug carrier. Arch Pharmacal Res 2004; 27(5): 562–569.

Peppas NA. Devices based on intelligent biopolymers for oral protein delivery. Int J Pharm 2004; 277(1–2): 11–17.

Bhalla HL, Menon MR, Gopal NGS. Radiation sterilization of polyethylene glycols. Int J Pharm 1983; 17: 351–355.

Smyth HF, Carpenter CP, Weil CS. The toxicology of the polyethylene glycols. J Am Pharm Assoc (Sci) 1950; 39: 349–354.

Tusing TW, Elsea JR, Sauveur AB. The chronic dermal toxicity of a series of polyethylene glycols. J Am Pharm Assoc (Sci) 1954; 43: 489–490.

Smyth HF, Carpenter CP, Weil CS. The chronic oral toxicology of the polyethylene glycols. J Am Pharm Assoc (Sci) 1955; 44: 27–30.

Fisher AA. Immediate and delayed allergic contact reactions to polyethylene glycol. Contact Dermatitis 1978; 4: 135–138.

Anonymous. Topical PEG in burn ointments. FDA Drug Bull

1982; 12: 25–26.

Sweetman SC, ed. Martindale: The Complete Drug Reference,

34th edn. London: Pharmaceutical Press, 2005: 1708–1709.

FAO/WHO. Evaluation of certain food additives. Twenty-third report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1980; No. 648.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3001.

General References

Donovan MD, Flynn GL, Amidon GL. Absorption of polyethylene glycols 600 through 2000: molecular weight dependence of gastrointestinal and nasal absorption. Pharm Res 1990; 7: 863–

867.

Mi YI, Wood J. The application and mechanisms of polyethylene glycol 8000 on stabilizing lactate dehydrogenase during lyophilization. PDA J Pharm Sci Technol 2004; 58(4): 192–202.

Union Carbide Corporation. Technical literature: Carbowax polyethy- lene glycols, 1986.

Van Dam J, Daenens P. Molecular weight identification of polyethylene glycols in pharmaceutical preparations by gel permeation chroma- tography. J Pharm Sci 1993; 82: 938–941.

Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci 1994; 83: 601– 606.

USPNF: Polyethylene oxide

Synonyms

Polyox; polyoxirane; polyoxyethylene.

Chemical Name and CAS Registry Number

Polyethylene oxide [25322-68-3]

Empirical Formula and Molecular Weight

See Table I.

Structural Formula

The USPNF 23 describes polyethylene oxide as a nonionic homopolymer of ethylene oxide, represented by the formula (CH2CH2O)n, where n represents the average number of oxyethylene groups. It may contain up to 3% of silicon dioxide.

Functional Category

Mucoadhesive; tablet binder; thickening agent.

Applications in Pharmaceutical Formulation or Technology

Polyethylene oxide can be used as a tablet binder at concentrations of 5–85%. The higher molecular weight grades provide delayed drug release via the hydrophilic matrix approach; see Table I.

The relationship between swelling capacity and molecular weight is a good guide when selecting products for use in immediate- or sustained-release matrix formulations; see Figure 1.

Polyethylene oxide has been shown to be an excellent mucoadhesive polymer.(1) Low levels of polyethylene oxide are effective thickeners, although alcohol is usually added to water- based formulations to provide improved viscosity stability; see Table II. Polyethylene oxide films demonstrate good lubricity when wet. This property has been utilized in the development of coatings for medical devices. Polyethylene oxide can be radiation crosslinked in solution to produce a hydrogel that can be used in wound care applications.

Description

White to off-white, free-flowing powder. Slight ammoniacal odor.

Figure 1: Swelling capacity of polyethylene oxide (Polyox WSR). Measured for four molecular weight grades; 28 mm tablets in 300 mL of water.

Table I: Number of repeat units and molecular weight as a function of polymer grade for polyethylene oxide.

Polyox grade Approximate number of repeating units Approximate molecular weight

WSR N-10 2 275 100 000

WSR N-80 4 500 200 000

WSR N-750 6 800 300 000

WSR N-3000 9 100 400 000

WSR 205 14 000 600 000

WSR 1105 20 000 900 000

WSR N-12K 23 000 1 000 000

WSR N-60K 45 000 2 000 000

WSR 301 90 000 4 000 000

WSR Coagulant 114 000 5 000 000

WSR 303 159 000 7 000 000

Note: molecular weight based on dilute viscosity measurements.

Table II: Polyethylene oxide viscosity at 258C (mPa s).

Polyox grade 5% solution 2% solution 1% solution

WSR N-10 30–50 — —

WSR N-80 55–90 — —

WSR N-750 600–1 200 — —

WSR N-3000 2 250–4 500 — —

WSR 205 4 500–8 800 — —

WSR 1105 8 800–17 600 — —

WSR N-12K — 400–800 —

WSR N-60K — 2 000–4 000 —

WSR 301 — — 1 650–5 500

WSR coagulant — — 5 500–7 500

WSR 303 — — 7 500–10 000

Note: all solution concentrations are based on the water content of the hydro-alcoholic solutions.

552 Polyethylene Oxide

Pharmacopeial Specifications

See Table III.

Table III: Pharmacopeial specifications for polyethylene oxide.

Test USPNF 23

Identification +

Loss on drying 41.0%

absorbed from the gastrointestinal tract but appears to be completely and rapidly eliminated. The resins are neither skin irritants nor sensitizers, and they do not cause eye irritation.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled.

Silicon dioxide and nonsilicon dioxide residue on ignition

42.0%

Regulatory Status

Silicon dioxide 43.0%

Heavy metals 40.001%

Free ethylene oxide 40.001%

Organic volatile impurities +

Viscosity +

Typical Properties

Angle of repose: 348 Density (true): 1.3 g/cm3 Melting point: 65–708C Moisture content: <1%

Solubility: polyethylene oxide is soluble in water and a number

of common organic solvents such as acetonitrile, chloro- form, and methylene chloride. It is insoluble in aliphatic hydrocarbons, ethylene glycol, and most alcohols.(2)

Viscosity (dynamic): see Table II.

Stability and Storage Conditions

Store in tightly sealed containers in a cool, dry place. Avoid exposure to high temperatures since this can result in reduction in viscosity.

Incompatibilities

Polyethylene oxide is incompatible with strong oxidizing agents.

Method of Manufacture

Polyethylene oxide is prepared by the polymerization of ethylene oxide using a suitable catalyst.(1)

Safety

Animal studies suggest that polyethylene oxide has a low level of toxicity regardless of the route of administration. It is poorly

Included in the FDA Inactive Ingredients Guide (sustained- release tablets). Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Bottenberg P, Cleymaet R, de Muynck C, et al. Development and testing of bioadhesive, fluoride-containing slow-release tablets for oral use. J Pharm Pharmacol 1991; 43: 457–464.

Bailey FE, Kolesky JV. Poly(ethylene oxide). London: Academic Press: 1976.

General References

Dhawan S, Varma M, Sinha VR. High molecular weight poly(ethylene oxide)-based drug delivery systems. Part 1: hydrogels and hydro- philic matrix systems. Pharm Technol 2005; 29(5): 72–74, 76–80. Union Carbide Corp. Technical literature: Polyox water soluble resin,

1998.

Yu DM, Amidon GL, Weiner ND, Goldberg AH. Viscoelastic proper- ties of poly(ethylene oxide) solution. J Pharm Sci 1994; 83: 1443– 1449.

BP: Methacrylic acid–ethyl acrylate copolymer (1 : 1) PhEur: Acidum methacrylicum et ethylis acrylas poly-

merisatum 1 : 1

Acidum methacrylicum et ethylis acrylas poly- merisatum 1 : 1 dispersio 30 per centum

Acidum methacrylicum et methylis methacrylas polymerisatum 1 : 1

Acidum methacrylicum et methylis methacrylas polymerisatum 1 : 2

Copolymerum methacrylatis butylati basicum Polyacrylatis dispersion 30 per centum

USPNF: Ammonio methacrylate copolymer Methacrylic acid copolymer Methacrylic acid copolymer dispersion

Note that three separate monographs applicable to polymetha- crylates are contained in the USPNF 23; see Section 9. Several different types of material are defined in the monographs. The PhEur 2005 contains four separate monographs applicable to polymethacrylates.

Synonyms

Acryl-EZE; Acryl-EZE MP; Eastacryl 30D; Eudragit; Kolli- coat MAE 30 D; Kollicoat MAE 30 DP; polymeric methacry- lates. See also Table I.

Chemical Name and CAS Registry Number

See Table I.

Empirical Formula and Molecular Weight

The PhEur 2005 describes methacrylic acid–ethyl acrylate copolymer (1 : 1) as a copolymer of methacrylic acid and ethyl acrylate having a mean relative molecular mass of about 250 000. The ratio of carboxylic groups to ester groups is about 1 : 1. It may contain suitable surfactants such as sodium dodecyl sulfate or polysorbate 80. An aqueous 30% w/v dispersion of this material is also defined in a separate monograph. Methacrylic acid–methyl methacrylate copolymer (1 : 1) is described in the PhEur 2005 as a copolymer of methacrylic acid and methyl methacrylate having a mean relative molecular mass of about 135 000. The ratio of carboxylic acid to ester groups is about 1 : 1. A further monograph in the PhEur 2005 describes methacrylic acid–methyl methacrylate copolymer (1 : 2), where the ratio of carboxylic acid to ester groups is about 1 : 2. The PhEur 2005 describes basic butylated methyacrylate copolymer as a copolymer of (2-dimethylami- noethyl) methacrylate, butyl methyacrylate, and methyl metha- crylate having a mean relative molecular mass of about 150 000. The ratio of (2-dimethylaminoethyl) methacrylate groups to butyl methyacrylate and methyl methacrylate groups is about 2 : 1 : 1. Polyacrylate dispersion (30 per cent) is described in the PhEur 2005 as a dispersion in water of a copolymer of ethyl acrylate and methyl methacrylate having a mean relative molecular mass of about 800 000. It may contain a suitable emulsifier.

The USPNF 23 describes methacrylic acid copolymer as a fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic ester. Three types of copolymers, namely Type A, Type B, and Type C, are defined in the monograph. They vary in their methacrylic acid content and solution viscosity. Type C may contain suitable surface-active agents. Two additional polymers, Type A (Eudragit RL) and Type B (Eudragit RS), also referred to as ammonio methacrylate copolymers, consisting of fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, are also described in the USPNF 23. A further monograph for an aqueous dispersion of Type C methacrylic acid copolymer is also defined; see Section 9.

Typically, the molecular weight of the polymer is 5100 000.

Structural Formula

For Eudragit E:

R1, R3 = CH3

R2 = CH2CH2N(CH3)2 R4 = CH3, C4H9

For Eudragit L and Eudragit S:

For Eudragit RL and Eudragit RS:

R1 = H, CH3

R2 = CH3, C2H5 R3 = CH3

R4 = CH2CH2N(CH )+Cl—

For Eudragit NE 30 D and Eudragit NE 40 D: R1, R3 = H, CH3

R2, R4 = CH3, C2H5

For Acryl-EZE and Acryl-EZE MP; Eudragit L 30 D-55 and Eudragit L 100-55, Eastacryl 30D, Kollicoat MAE 30 D and Kollicoat MAE 30 DP:

R1, R3 = H, CH3 R2 = H

R4 = CH3, C2H5

554 Polymethacrylates

Table I: Chemical name and CAS Registry Number of polymethacrylates.

Chemical name Trade name Company name CAS number

Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 : 2 : 1

Eudragit E 100 Ro¨hm GmbH [24938-16-7]

Eudragit E 12.5 Ro¨hm GmbH

Eudragit E PO Ro¨hm GmbH

Poly(ethyl acrylate, methyl methacrylate) 2 : 1 Eudragit NE 30 D Ro¨hm GmbH [9010-88-2]

Eudragit NE 40 D Ro¨hm GmbH

Poly(methacrylic acid, methyl methacrylate) 1 : 1 Eudragit L 100 Ro¨hm GmbH [25806-15-1]

Eudragit L 12.5 Ro¨hm GmbH

Eudragit L 12.5 P Ro¨hm GmbH

Poly(methacrylic acid, ethyl acrylate) 1 : 1 Acryl-EZE Colorcon [25212-88-8]

Acryl-EZE MP Colorcon

Eudragit L 30 D-55 Ro¨hm GmbH

Eudragit L 100-55 Ro¨hm GmbH

Eastacryl 30D Eastman Chemical Kollicoat MAE 30 D BASF Fine Chemicals Kollicoat MAE 30 DP BASF Fine Chemicals

Poly(methacrylic acid, methyl methacrylate) 1 : 2 Eudragit S 100 Ro¨hm GmbH [25086-15-1]

Eudragit S 12.5 Ro¨hm GmbH

Eudragit S 12.5 P Ro¨hm GmbH

Poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3:1 Eudragit FS 30D Ro¨hm GmbH [26936-24-3]

Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2

Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1

Eudragit RL 100 Ro¨hm GmbH [33434-24-1]

Eudragit RL PO Ro¨hm GmbH

Eudragit RL 30 D Ro¨hm GmbH

Eudragit RL 12.5 Ro¨hm GmbH

Eudragit RD 100 Ro¨hm GmbH

Eudragit RS 100 Ro¨hm GmbH [33434-24-1]

Eudragit RS PO Ro¨hm GmbH

Eudragit RS 30 D Ro¨hm GmbH

Eudragit RS 12.5 Ro¨hm GmbH

Functional Category

Film former; tablet binder; tablet diluent.

Applications in Pharmaceutical Formulation or Technology

Polymethacrylates are primarily used in oral capsule and tablet formulations as film-coating agents.(1–17) Depending on the type of polymer used, films of different solubility characteristics can be produced; see Table II.

Eudragit E is used as a plain or insulating film former; it is soluble in gastric fluid below pH 5. In contrast, Eudragit L, S and FS types are used as enteric coating agents because they are resistant to gastric fluid. Different types are available that are soluble at different pH values: e.g. Eudragit L is soluble at pH

> 6; Eudragit S and FS are soluble at pH > 7.

Eudragit RL, RS, RD 100, NE 30 D and NE 40 D are used

to form water-insoluble film coats for sustained-release products. Eudragit RL films are more permeable than those of Eudragit RS, and films of varying permeability can be obtained by mixing the two types together.

Eudragit L 30 D-55 is used as an enteric coating film former for solid-dosage forms. The coating is resistant to gastric juice but dissolves readily at above pH 5.5.

Eudragit L 100-55 is an alternative to Eudragit L 30 D-55.

It is commercially available as a redispersible powder.

Acryl-EZE and Acryl-EZE MP are also commercially available as redispersible powder forms, which are designed for enteric coating of tablets and beads, respectively.

Eastacryl 30 D, Kollicoat MAE 30 D, and Kollicoat MAE

30 DP, are aqueous dispersions of methacrylic acid–ethyl acrylate copolymers. They are also used as enteric coatings for solid-dosage forms.

Polymethacrylates are also used as binders in both aqueous and organic wet-granulation processes. Larger quantities (5–20%) of dry polymer are used to control the release of an active substance from a tablet matrix. Solid polymers may be used in direct-compression processes in quantities of 10–50%. Polymethacrylate polymers may additionally be used to form the matrix layers of transdermal delivery systems and have also been used to prepare novel gel formulations for rectal

administration.(18)

See also Section 18.

Description

Polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several different types are commercially available and may be obtained as the dry powder, as an aqueous dispersion, or as an organic solution. A (60 : 40) mixture of acetone and propan-2-ol is most commonly used as the organic solvent. See Tables I and III.

Eudragit E is cationic polymer based on dimethylamino- ethyl methacrylate and other neutral methacrylic acid esters. It

Polymethacrylates 555

Table II: Summary of properties and uses of commercially available polymethacrylates.

Eudragit FS 30D Aqueous dispersion 30% Water Soluble in intestinal fluid

from pH 7

Enteric coatings

matrix

Eudragit NE 40 D Aqueous dispersion 40% Water Swellable, permeable Sustained release, tablet

matrix

Eastacryl (Eastman Chemical)

Eastacryl 30 D Aqueous dispersion 30% Water Soluble in intestinal fluid

from pH 5.5

Enteric coatings

Kollicoat (BASF Fine Chemicals)

Kollicoat 30 D Aqueous dispersion 30% Water Soluble in intestinal fluid

from pH 5.5

Kollicoat 30 DP Aqueous dispersion 30% Water Soluble in intestinal fluid

from pH 5.5

Enteric coatings Enteric coatings

Acryl-EZE (Colorcon)

Acryl-EZE Powder 95% Water Soluble in intestinal fluid

from pH 5.5

Acryl-EZE MP Aqueous dispersion 95% Water Soluble in intestinal fluid

from pH 5.5

Enteric coatings Enteric coatings

Note: Recommended plasticizers for the above polymers include dibutyl phthalate, polyethylene glycols, triethyl citrate, triacetin, and 1,2-propylene glycol. The recommended concentration of the plasticizer is approximately 10–25% plasticizer (based on the dry polymer weight). A plasticizer is not necessary with Eudragit E 12.5, Eudragit E 100 and Eudragit NE 30 D.

556 Polymethacrylates

Table III: Solubility of commercially available polymethacrylates in various solvents.

Type Solvent

Acetone and alcohols(a) Dichloromethane Ethyl acetate 1 N HCl 1 N NaOH Petroleum ether Water

Eudragit (Ro¨hm GmbH)

Eudragit E 12.5 M M M M — M —

Eudragit E 100 S S S — — I I

Eudragit L 12.5 P M M M — M P P

Eudragit L 12.5 M M M — M P P

Eudragit L 100-55 S I I — S I I

Eudragit L 100 S I I — S I I

Eudragit L 30 D-55(b) M(c) — — M — M —

Eudragit S 12.5 P M M M — M P P

Eudragit S 12.5 M M M — M P P

Eudragit S 100 S I I — S I I

Eudragit RL 12.5 M M M — — P M

Eudragit RL 100 S S S — — I I

Eudragit RL PO S S S — I I I

Eudragit RL 30 D(b) M(c) M M — I I M

Eudragit RS 12.5 M M M — — P M

Eudragit RS 100 S S S — — I I

Eudragit RS PO S S S — I I I

Kollicoat (BASF Fine Chemicals)

S = soluble; M = miscible; I = insoluble or immiscible; P = precipitates.

(a) Alcohols including ethanol (95%), methanol, and propan-2-ol.

(b) Supplied as a milky-white aqueous dispersion.

1 part of Eudragit RL 30 D or of Eudragit RS 30 D dissolves completely in 5 parts acetone, ethanol (95%), or propan-2-ol to form a clear or slightly turbid solution. However, when mixed in a ratio of 1 : 5 with methanol, Eudragit RL 30 D dissolves completely, whereas Eudragit RS 30 D dissolves only partially.

is soluble in gastric fluid as well as in weakly acidic buffer solutions (up to pH ≈ 5). Eudragit E is available as a 12.5% ready-to-use solution in propan-2-ol–acetone (60 : 40). It is light yellow in color with the characteristic odor of the solvents. Solvent-free granules contain ≈98% dried weight content of Eudragit E. Eudragit E PO is a white free-flowing powder with at least 95% of dry polymer.

Eudragit L and S, also referred to as methacrylic acid copolymers in the USPNF 23 monograph, are anionic copolymerization products of methacrylic acid and methyl methacrylate. The ratio of free carboxyl groups to the ester is approximately 1 : 1 in Eudragit L (Type A) and approximately 1:2 in Eudragit S (Type B). Both polymers are readily soluble in neutral to weakly alkaline conditions (pH 6–7) and form salts with alkalis, thus affording film coats that are resistant to gastric media but soluble in intestinal fluid. They are available as a 12.5% solution in propan-2-ol without plasticizer (Eudragit L 12.5 and S 12.5); and as a 12.5% ready-to-use solution in propan-2-ol with 1.25% dibutyl phthalate as plasticizer (Eudragit L 12.5 P and S 12.5 P). Solutions are colorless, with the characteristic odor of the solvent. Eudragit L-100 and Eudragit S-100 are white free-flowing powders with at least 95% of dry polymers.

Eudragit FS 30D is the aqueous dispersion of an anionic copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid. The ratio of free carboxyl groups to ester groups is approximately 1 : 10. It has been designed for the use in enteric-coated solid-dosage forms and dissolves in aqueous

systems at pH >7.

Eudragit RL and Eudragit RS, also referred to as ammonio

methacrylate copolymers in the USPNF 23 monograph, are copolymers synthesized from acrylic acid and methacrylic acid esters, with Eudragit RL (Type A) having 10% of functional quaternary ammonium groups and Eudragit RS (Type B) having 5% of functional quaternary ammonium groups. The ammonium groups are present as salts and give rise to pH- independent permeability of the polymers. Both polymers are water-insoluble, and films prepared from Eudragit RL are freely permeable to water, whereas, films prepared from Eudragit RS are only slightly permeable to water. They are available as 12.5% ready-to-use solutions in propan-2-ol– acetone (60 : 40). Solutions are colorless or slightly yellow in color, and may be clear or slightly turbid; they have an odor characteristic of the solvents. Solvent-free granules (Eudragit RL 100 and Eudragit RS 100) contain 597% of the dried weight content of the polymer.

Polymethacrylates 557

Table IV: Specifications from PhEur 2005.

Test PhEur 2005

Methacrylic Methacrylic Methacrylic Methacrylic Basic Polyacrylate

acid–ethyl acid–ethyl acid–methyl acid–methyl butylated dispersion 30%(f)

acrylate copolymer (1 : 1)(a) acrylate copolymer

(1 : 1) methacrylate copolymer

(1 : 1)(c) methacrylate copolymer

(1 : 2)(d) methacrylate copolymer(e)

dispersion 30%(b)

Identification + + + + + +

Characters + + + + + +

Appearance of a film + + + + + +

Apparent viscosity 100–200 mPa s 415 mPa s 50–200 mPa s 50–200 mPa s 3–6 mPa s 450 mPa s

Particulate matter — 41.0% — — — 40.5%

Limit of monomers — — — — 40.3% 4100 ppm

Ethyl acrylate and 40.1% 40.1% — — — —

methacrylic acid

Methyl methacrylate and — — 40.1% 40.1% — —

methacrylic acid

Residue on evaporation — 0.285–0.315 g — — — 0.285–0.315 g

Loss on drying 45.0% — 45.0% 45.0% 42.0% —

Heavy metals — — — — 420 ppm 420 ppm

Sulfated ash 40.4% 40.2% 40.1% 40.1% 40.1% 40.4%

Microbial contamination — 4103/g — — — 4103/g

Assay Methacrylic Methacrylic Methacrylic Methacrylic Dimethylaminoethyl Residue on

acid units acid units acid units acid units units evaporation

46.0–50.6% 46.0–50.6% 46.0–50.6% 27.6–30.7% 20.8–25.5% 28.5%–31.5%

(a) Corresponds to Eudragit L100-55.

(b) Corresponds to Eudragit L 30D-55.

(d) Corresponds to Eudragit S.

(e) Corresponds to Eudragit E.

(f) Corresponds to Eudragit NE 30D.

Eudragit RL PO and Eudragit RS PO are fine, white powders with a slight amine-like odor. They are character- istically the same polymers as Eudragit RL and RS. They contain 597% of dry polymer.

Eudragit RL 30 D and Eudragit RS 30 D are aqueous dispersions of copolymers of acrylic acid and methacrylic acid esters with a low content of quaternary ammonium groups. The dispersions contain 30% polymer. The quaternary groups occur as salts and are responsible for the permeability of films made from these polymers. Films prepared from Eudragit RL 30 D are readily permeable to water and to dissolved active substances, whereas films prepared from Eudragit RS 30 D are less permeable to water. Film coatings prepared from both polymers give pH-independent release of active substance. Plasticizers are usually added to improve film properties.

Eudragit RD100 is in the powder form, which can be re- dispersed in water and used as rapid disintegrating films. The composition for Eudragit RD100 is Eudragit RL100 and carboxymethylcellulose sodium (90 : 10).

Eudragit NE 30 D and Eudragit NE 40 D are aqueous dispersions of a neutral copolymer consisting of poly- methacrylic acid esters. The dispersions are milky-white liquids of low viscosity and have a weak aromatic odor. Films prepared from the lacquer swell in water, to which they become permeable. Thus, films produced are insoluble in water, but give pH-independent drug release.

Eudragit L 30 D-55, is an aqueous dispersion of an anionic copolymer based on methacrylic acid and ethyl acrylate. The

copolymer corresponds to USPNF 23 methacrylic acid copo- lymer, Type C. The ratio of free-carboxyl groups to ester groups is 1 : 1. Films prepared from the copolymers dissolve above pH 5.5, forming salts with alkalis, thus affording coatings that are insoluble in gastric media but soluble in the small intestine.

Eastacryl 30D, Kollicoat MAE 30 D, and Kollicoat MAE 30 DP are also aqueous dispersions of the anionic copolymer based on methacrylic acid and ethyl acrylate. The copolymer also corresponds to USPNF 23 methacrylic acid copolymer, Type C. The ratio of free-carboxyl groups to ester groups is 1 : 1. Films prepared from the copolymers dissolve above pH 5.5, forming salts with alkalis, thus affording coatings that are insoluble in gastric media, but soluble in the small intestine.

Eudragit L 100-55 (prepared by spray-drying Eudragit L 30 D-55) is a white, free-flowing powder that is redispersible in water to form a latex that has properties similar to those of Eudragit L 30 D-55.

Acryl-EZE and Acryl-EZE MP are also commercially available as redispersible powder forms, which are designed for enteric coating of tablets and beads, respectively.

Pharmacopeial Specifications

Specifications for polymethacrylates from the PhEur 2005 are shown in Table IV and those from the USPNF 23 in Table V.

558 Polymethacrylates

Typical Properties

Acid value:

300–330 for Eudragit L 12.5, L 12.5 P, L 100, L 30 D-55, L

100-55, Eastacryl 30D, Kollicoat MAE 30 D, and Kollicoat MAE 30 DP.

180–200 for Eudragit S 12.5, S 12.5 P, and S 100.

Alkali value:

162–198 for Eudragit E 12.5 and E 100;

23.9–32.3 for Eudragit RL 12.5, RL 100, and RL PO;

27.5–31.7 for Eudragit RL 30 D;

12.1–18.3 for Eudragit RS 12.5, RS 100, and RS PO;

16.5–22.3 for Eudragit RS 30 D.

Density (bulk): 0.390 g/cm3 Density (tapped): 0.424 g/cm3 Density (true):

0.811–0.821 g/cm3 for Eudragit E;

0.83–0.85 g/cm3 for Eudragit L, S 12.5 and 12.5 P; 1.058–1.068 g/cm3 for Eudragit FS 30D; 0.831–0.852 g/cm3 for Eudragit L, S 100; 1.062–1.072 g/cm3 for Eudragit L 30 D-55; 0.821–0.841 g/cm3 for Eudragit L 100-55; 0.816–0.836 g/cm3 for Eudragit RL and RS 12.5; 0.816–0.836 g/cm3 for Eudragit RL and RS PO; 1.047–1.057 g/cm3 for Eudragit RL and RS 30 D; 1.037–1.047 g/cm3 for Eudragit NE 30D; 1.062–1.072 g/cm3 for Eastacryl 30D;

1.062–1.072 g/cm3 for Kollicoat MAE 30 D and Kollicoat MAE 30 DP.

Refractive index:

n20 = 1.38–1.385 for Eudragit E;

n20 = 1.39–1.395 for Eudragit L and S;

n20 = 1.387–1.392 for Eudragit L 100-55; n20 = 1.38–1.385 for Eudragit RL and RS.

Solubility: see Table II.

Viscosity (dynamic):

3–12 mPa s for Eudragit E;

450 mPa s for Eudragit NE 30D; 50–200 mPa s for Eudragit L and S; 420 mPa s for Eudragit FS 30D; 415 mPa s for Eudragit L 30 D-55;

100–200 mPa s for Eudragit L 100-55; 415 mPa s for Eudragit RL and RS; 4200 mPa s for Eudragit RL and RS 30D;

415 mPa s for Kollicoat MAE 30 D and Kollicoat MAE 30 DP;

145 mPa s for Eastacryl 30D.

Stability and Storage Conditions

Dry powder polymer forms are stable at temperatures less than 308C. Above this temperature, powders tend to form clumps, although this does not affect the quality of the substance and the clumps can readily be broken up. Dry powders are stable for at least 3 years if stored in a tightly closed container at less than 308C.

Dispersions are sensitive to extreme temperatures and phase separation occurs below 08C. Dispersions should therefore be stored at temperatures between 5 and 258C and are stable for at least 18 months after shipping from the manufacturer’s warehouse if stored in a tightly closed container at the above conditions.

Incompatibilities

Incompatibilities occur with certain polymethacrylate disper- sions depending upon the ionic and physical properties of the

polymer and solvent. For example, coagulation may be caused by soluble electrolytes, pH changes, some organic solvents, and extremes of temperature; see Table II. For example, dispersions of Eudragit L 30 D, RL 30 D, L 100-55, and RS 30 D are incompatible with magnesium stearate. Eastacryl 30D, Kolli- coat MAE 30 D, and Kollicoat MAE 30 DP are also incompatible with magnesium stearate.

Interactions between polymethacrylates and some drugs can occur, although solid polymethacrylates and organic solutions are generally more compatible than aqueous dispersions.

Method of Manufacture

Prepared by the polymerization of acrylic and methacrylic acids or their esters, e.g. butyl ester or dimethylaminoethyl ester.

Safety

Polymethacrylate copolymers are widely used as film-coating materials in oral pharmaceutical formulations. They are also used in topical formulations and are generally regarded as nontoxic and nonirritant materials.

A daily intake of 2 mg/kg body-weight of Eudragit (equivalent to approximately 150 mg for an average adult) may be regarded as essentially safe in humans.

See also Section 17.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Methyl methacrylate; poly(methyl methacrylate).

Methyl methacrylate Empirical formula: C5H8O2 Molecular weight: 100.13

CAS number: [80-62-6]

Synonyms: methacrylic acid, methyl ester; methyl 2-methacryl- ate; methyl 2-methylpropenoate; MME.

Safety:

LD50 (dog, SC): 4.5 g/kg LD50 (mouse, IP): 1 g/kg LD50 (mouse, oral): 5.2 g/kg

Polymethacrylates 559

Table V: Specifications from USPNF 23

Test USPNF 23

Ammonio methacrylate copolymer(a) Methacrylic acid copolymer(b) Methacrylic acid copolymer dispersion(c)

Identification + + +

Viscosity

Type A 415 mPa s 50–200 mPa s —

Type B 415 mPa s 50–200 mPa s —

Type C — 100–200 mPa s 415 mPa s

Loss on drying

Type A 43.0% 45.0% —

Type B 43.0% 45.0% —

Type C — 45.0% 68.5–71.5%(d)

Residue on ignition

Type A 40.1% 40.1% —

Type B 40.1% 40.1% —

Type C — 40.4% 40.2%(d)

Heavy metals 40.002% 40.002% 40.002%(d)

Organic volatile impurities — + —

Limit of monomers — 40.05% 40.01%

Limit of methyl methacrylate 40.005% — —

Limit of ethyl acrylate

Coagulum content 40.025%

— —

41%(d)

Assay (dried basis) Ammonio methacrylate units Methacrylic acid units Methacrylic acid units

Type A 8.85–11.96% 46.0–50.6% —

Type B 4.48–6.77% 27.6–30.7% —

Type C — 46.0–50.6% 46.0–50.6%

(a) Corresponds to Eudragit RL and RS.

(b) Corresponds to Eudragit L, S and L100-55.

(d) Calculated based on undried dispersion basis.

LD50 (mouse, SC): 6.3 g/kg LD50 (rat, IP): 1.33 g/kg LD50 (rat, SC): 7.5 g/kg

Comments: methyl methacrylate forms the basis of acrylic bone cements used in orthopedic surgery.

Poly(methyl methacrylate)

Empirical formula: (C5H8O2)n

Synonyms: methyl methacrylate polymer; PMMA.

Comments: poly(methyl methacrylate) has been used as a material for intraocular lenses, for denture bases, and as a cement for dental prostheses.

Comments

A number of different polymethacrylates are commercially available that have different applications and properties; see Table II.

For spray coating, polymer solutions and dispersions should be diluted with suitable solvents. Some products need the addition of a plasticizer such as dibutyl sebacate, dibutyl phthalate, glyceryl triacetate, or polyethylene glycol. Different types of plasticizer may be mixed to optimize the polymer properties for special requirements.

Specific References

Lehmann K, Dreher D. The use of aqueous synthetic-polymer dispersions for coating pharmaceutical dosage forms. Drugs Made Ger 1973; 16: 126, 131, 132, 134, 136.

Lehmann K. Acrylic coatings in controlled release tablet manu- facture I. Manuf Chem Aerosol News 1973; 44(5): 36–38.

Lehmann K. Acrylic coatings in controlled release tablet manu- facture II. Manuf Chem Aerosol News 1973; 44(6): 39–41.

Lehmann K. Polymer coating of tablets – a versatile technique.

Manuf Chem Aerosol News 1974; 45(5): 48, 50.

Gurny R, Guitard P, Buri P, Sucker H. Realization and theoretical development of controlled-release drug forms using methacrylate films 3: preparation and characterization of controlled-release drug forms [in French]. Pharm Acta Helv 1977; 52: 182–187.

Lehmann K, Dreher D. Coating of tablets and small particles with acrylic resins by fluid bed technology. Int J Pharm Technol Prod Manuf 1981; 2(4): 31–43.

Dew MJ, Hughes PJ, Lee MG, et al. An oral preparation to release drugs in the human colon. Br J Clin Pharmacol 1982; 14: 405– 408.

Lehmann K. Formulation of controlled release tablets with acrylic resins. Acta Pharm Fenn 1984; 93: 55–74.

Lehmann K. Acrylic latices from redispersible powders for peroral and transdermal drug formulations. Drug Dev Ind Pharm 1986; 12: 265–287.

Lehmann K, Dreher D. Mixtures of aqueous polymethacrylate dispersions for drug coating. Drugs Made Ger 1988; 31: 101–102.

Beckert TE, Lehmann K, Schmidt PC. Compression of enteric coated pellets to disintegrating tablets. Int J Pharm 1996; 143: 13–

23.

Vecchio C, Fabiani F, Gazzaniga A. Use of colloidal silica as a separating agent in film forming processes performed with aqueous dispersion of acrylic resins. Drug Dev Ind Pharm 1995; 21(15): 1781–1787.

Okor RS, Obi CE. Drug release through aqueous-based film coatings of acrylate-methacrylate, a water-insoluble copolymer. Int J Pharm 1990; 58: 89–91.

Caneron CG, McGinity JW. Controlled-release theophylline tablet formulations containing acrylic resins, part 3: influence of filler excipient. Drug Dev Ind Pharm 1987; 13(2): 303–318.

560 Polymethacrylates

Jovanovic M, Jovicic G, Duvic Z, et al. Effect of fillers and lubricants on acetylsalicylic acid release kinetics from eudragit matrix tablets. Drug Dev Ind Pharm 1997; 23(6): 595–602.

Gupta VK, Beckert TE, Price JC. A novel pH- and time-based multi-unit potential colonic drug delivery system. I. Development. Int J Pharm 2001; 213: 83–91.

Gupta VK, Assmus MW, Beckert TE, Price JC. A novel pH- and time-based multi-unit potential colonic drug delivery system. II Optimization of multiple response variables. Int J Pharm 2001; 213: 93–102.

Umejima H, Kim N-S, Ito T, et al. Preparation and evaluation of Eudragit gels VI: in vivo evaluation of Eudispert rectal hydrogel and Xerogel containing salicylamide. J Pharm Sci 1993; 82: 195– 199.

Routledge R. Possible hazard of contact lens manufacture [letter].

Br Med J 1973; 1: 487–488.

Burchman S, Wheater RH. Hazard of methyl methacrylate to operating room personnel. J Am Med Assoc 1976; 235: 2652.

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: Health and Safety Executive, 2002.

General References

McGinity JW. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, 2nd edn. New York: Marcel Dekker, 1997.

Ro¨ hm Pharma GmbH. Eudragit. http://www.roehm.com/en/ pharmapolymers (accessed 20 May 2005).

Authors

RK Chang, Y Peng, AJ Shukla.

Date of Revision

20 May 2005.

Poly(methyl vinyl ether/maleic anhydride)

Nonproprietary Names

None adopted.

Synonyms

Butyl ester of poly(methylvinyl ether–co-maleic anhydride);

Table II: Molecular weights of selected commercially available copolymers of poly(methylvinyl ether/maleic anhydride)

Grade Approximate molecular weight

Gantrez AN-119 200 000

Gantrez AN-903 800 000

calcium and sodium salts of poly(methylvinyl ether–co-maleic Gantrez AN-139 1 000 000

anhydride); Gantrez AN-119; Gantrez AN-139; Gantrez AN- Gantrez AN-169 2 000 000

149; Gantrez AN-169; Gantrez AN-179; Gantrez AN-903; Gantrez S-96 700 000

Gantrez ES-225; Gantrez ES-425; Gantrez S-95; Gantrez S-96; Gantrez S-97 (powder) 1 200 000

Gantrez S-97; Gantrez MS-955. Gantrez S-97 (solution) 1 500 000

Gantrez MS-995 1 000 000

Chemical Name and CAS Registry Number

See Table I.

Empirical Formula and Molecular Weight

(C4H2O3·C3H6O)x See Table II.

Structural Formula

See Section 4.

Functional Category

Bioadhesive; color dispersant; complexing agent; emulsion stabilizer; film former; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Poly(methylvinyl ether/maleic anhydride) copolymers and derivatives are used in denture adhesive bases,(1) controlled- release coatings, enteric coatings, ostomy adhesives,(2) trans- dermal patches,(3) toothpastes,(4) mouthwashes,(5) and trans- dermal gels.(6,7) Gantrez AN-119 has been used to manufacture

Gantrez ES-225 100 000–150 000

Gantrez ES-425 90 000–150 000

specific bioadhesive ligand-nanoparticle conjugates(8) to aid gastrointestinal retention for oral drug delivery applications. More recently Gantrez has been utilized to develop novel polyethylene surface-modified medical devices with enhanced hydrophilicity and wettability.(9)

Description

In the solid state, poly(methylvinyl ether/maleic anhydride) copolymers are a white to off-white free flowing, odorless, hygroscopic powders. In solution, poly(methylvinyl ether/ maleic anhydride) is a slightly hazy, odorless, viscous liquid.

Pharmacopeial Specifications

—

Typical Properties

See Table III.

Table I: Chemical name and CAS registry number for poly(methylvinyl ether/maleic anhydride) copolymers and derivatives.

Chemical name Trade name CAS number

Poly(methylvinyl ether/maleic anhydride) Gantrez AN-119 [9011-16-9]

Poly(methylvinyl ether/maleic acid) Gantrez S-95 [25153-40-6]

Gantrez S-96

Gantrez S-97

Monoethyl ester of poly(methylvinyl ether/maleic acid) (48–52%) in Gantrez ES-225 50% Alcoholic Solution [25087-06-3] [64-17-5]

ethanol (48–52%)

Mixture of monoethyl ester of poly(methylvinyl ether/maleic acid) and monobutyl ester of poly(methylvinyl ether/maleic acid) (48–52%) in ethanol (43–47%) and n-butyl alcohol (≈5%)

Gantrez ES-425 50% Alcoholic Solution [25087-06-3] [25119-68-0]

[64-17-5]

[200-751-6]

Mixed sodium/calcium salts of poly(methylvinyl ether/maleic anhydride) Gantrez MS-955 [62386-95-2]

562 Poly(methyl vinyl ether/maleic anhydride)

Table III: Typical physical properties of selected commercially available copolymers of poly(methylvinyl ether/maleic anhydride)

Grade Specific viscosity (1% in MEK) Tg (8C) Specific gravity (258C, 5% solids) Bulk density (g/cm3) Polydispersity (Mn/Mw) Moisture content (% w/w) Viscosity (mPa s) of 5% w/w solution at 258C Dissociation constant

Gantrez AN copolymers

AN-119 0.1–0.5 152 1.018 0.34 2.74 <1 15 —

AN-903 0.8–1.2 156 1.017 0.33 — — 30 —

AN-139 1.0–1.5 151 1.016 0.33 3.47 <1 40 —

AN-149 1.5–2.5 153 1.017 0.35 2.58 <1 45 —

AN-169 2.5–3.5 154 1.017 0.32 2.06 <1 85 —

AN-179 3.5–5.0 154 1.017 0.33 2.12 <1 135 —

Gantrez S copolymers

S-95 1.0–2.0 139 1.015 — 2.71 417 20 3.51–6.41

S-96 Solution ≈4.0 — — — — 86–88 150 3.51–6.41

S-97 4.0–10.0 143 1.015 — 2.06 46 70 3.47–6.47

S-97 Solution 4.0–10.0 — — — — 86–88 1000 3.50–6.50

Gantrez ES and MS copolymers

ES-225 0.36–0.45 102 0.983 — 2.5–3.0 40.5 18,800 5.33

ES-425 0.37–0.45 96 0.977 — 2.5–3.4 40.5 14,400 5.28

MS-955 — — 1.061(a) — 2.3 415 700–3000(b) —

(a) 13% solids at 308C.

(b) Viscosity of 11.1% solids aqueous solution.

Stability and Storage Conditions

Poly(methylvinyl ether/maleic anhydride) and related free acids are hygroscopic powders and therefore excessive exposure to moisture should be avoided. Aqueous solutions exhibit decreases in viscosity upon exposure to UV light. Poly(methyl- vinyl ether/maleic anhydride) should be stored in a cool, dry place out of direct sunlight.

Incompatibilities

Poly(methylvinyl ether/maleic anhydride) and copolymers are incompatible with strong oxidizing agents and reducing agents, concentrated nitric acid, sulfuric acid, nitrofoam, oleum, potassium t-butoxide, aluminum, aluminum triisopropoxide, and crotonaldehyde. In addition, the anhydride will hydrolyze in water to form a water-soluble free acid that can subsequently be ionized to form salts in the presence of cations (Na+, Zn2+, Ca2+, and Al3+). Excessive addition of bivalent and trivalent metal ions to aqueous solution will result in precipitation, particularly in solutions containing high polymer concentra- tions.

Method of Manufacture

Poly(methylvinyl ether/maleic anhydride) and copolymers are manufactured from methylvinyl ether and maleic anhydride. The S, ES, and MS grades of Gantrez are manufactured by dispersing AN copolymers in a number of different solvents or salt solutions.(10)

Safety

Poly(methylvinyl ether/maleic anhydride) and copolymers are widely used in a diverse range of topical and oral pharmaceu- tical formulations.(11) These copolymers are generally regarded as nontoxic and nonirritant. Moreover, the dry powders and aqueous solutions are nonirritating with the exception of ES, MS, and A grades, which are irritating to the eye and may cause tissue damage.

LD50 (rat, oral): 8 g/kg (Gantrez AN-130 Powder)(10) LD50 (rat, oral): 40 ml/kg (Gantrez AN-139 20% w/w aqueous solution)

LD50 (rat, oral): <25.6 g/kg (Gantrez ES-225)

LD50 (rat, oral): 25.6 g/kg (Gantrez ES-425 40% w/v

corn oil solution)

LD50 (rat, oral): 25.6 g/kg (Gantrez MS-955 20% aqueous solution)

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive dust generation should be avoided when using powders, and an appropriate ventilation area and dust mask are recommended. Hand and eye protection is also recommended. The A, ES, and MS copolymers are extremely irritating to the eyes and a NIOSH- approved respirator and suitable eye protection are recom- mended when using Gantrez ES-435, Gantrez ES-225, and Gantrez A-425.

Regulatory Status

GRAS listed. Included in nonparenteral medicines licensed in the UK.

Shay K. The retention of complete dentures. In: Zarb GA, Bolender CL, Carlsson GE, Boucher CO, eds. Boucher’s Prosthodontic

Poly(methyl vinyl ether/maleic anhydride) 563

Treatment for Edentulous Patients. Toronto, Ontario: Mosby, 1997: 400–411.

Scalf BS, Fowler JF. Peristomal allergic contact dermatitis due to Gantrez in stomadhesive paste. J Am Acad Dermatol 2000; 42: 355–356.

Woolfson AD, McCafferty DF, Moss GP. Development and characterization of a moisture-activated bioadhesive drug delivery system for percutaneous local anesthesia. Int J Pharm 1998; 169: 83–94.

Busscher HJ, White DJ, Kamminga-Rasker HJ, Van der Mei HC. A surface physicochemical rationale for calculus formation in the oral cavity. J Cryst Growth 2004; 261: 87–92.

Kockisch S, Rees GD, Young SA, et al. A direct-staining method to evaluate the mucoadhesion of polymers from aqueous dispersion. J Control Release 2001; 77: 1–6.

Jones DS, Lawlor MS, Woolfson AD. Examination of the flow rheological and textural properties of polymer gels composed of poly(methylvinylether–co-maleic anhydride) and poly(vinylpyrro- lidone): rheological and mathematical interpretation of textural parameters. J Pharm Sci 2002; 91(9): 2090–2101.

Jones DS, Lawlor MS, Woolson AD. Rheological and mucoadhe- sive characterization of polymeric systems composed of poly(- methylvinylether–co-maleic anhydride) and poly(vinylpyrrolidone) designed as platforms for topical drug delivery. J Pharm Sci 2003; 92(5): 995–1007.

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