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Melting point: polydextrose is an amorphous polymer that does not have a melting range. However, it can undergo a viscosity transition at a temperature as low as 150–1608C. Moisture content: at relative humidities above approximately 60%, polydextrose absorbs significant amounts of moisture;

see Section 11. See also Figure 1.

Refractive index: n20= 1.3477 (10% w/v aqueous solution)

Solubility: completely miscible in water. Sparingly soluble to insoluble in most organic solvents. Polydextrose has a higher water solubility than most carbohydrates and polyols, allowing the preparation of 80% w/v solutions at 208C. Polydextrose is soluble in ethanol and only partially soluble in glycerin and propylene glycol.

Viscosity (dynamic): polydextrose solutions behave as New- tonian fluids. Polydextrose has a higher viscosity than sucrose or sorbitol at equivalent temperatures. This characteristic enables polydextrose to provide the desirable mouthfeel and textural qualities that are important when formulating syrups and viscous solutions. See Figure 2.

Stability and Storage Conditions

Polydextrose is hygroscopic and absorbs significant amounts of moisture at relative humidities greater than 60%. Under dry storage conditions it has good stability.

The bulk material should be stored in a cool, dry place in well-closed containers.

Incompatibilities

Incompatible with oxidizing agents, strong acids, and alkalis, forming a brown coloration and depolymerizing.

Method of Manufacture

Dextrose and sorbitol undergo a catalytic condensation reaction with an acid. Further purification may be performed to

Polydextrose 543

However, excessive consumption of non-digestible carbohy- drates, such as polydextrose, can lead to gastrointestinal distress. After evaluating a series of clinical studies, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the European Commission Scientific Committee for Food (EC/ SCF) concluded that polydextrose was better tolerated than other digestible carbohydrates such as polyols. The committee concluded that polydextrose has a mean laxative threshold of approximately 90 g/day (1.3 g/kg body-weight) or 50 g as a single dose.(3) See also Section 18.

LD50 (mouse, oral): >30 g/kg LD50 (rat, oral): >15 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Polydextrose may be irritant to the eyes. Eye protection and gloves are recommended. Conventional dust-control practices should be employed.

Figure 1: Moisture content of polydextrose at 208C.

Figure 2: Viscosity of polydextrose solutions at 258C at various concentrations.

Q: Sucrose

&: Polydextrose

□: Sorbitol

remove acidity and flavor notes generated during the con- densation.

Safety

Polydextrose is used in oral pharmaceutical applications, food products, and confectionery and is generally regarded as a relatively nontoxic and nonirritant material.(1,2)

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral tablets). Included in non-parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Dextrose.

Comments

Polydextrose is a randomly bonded polymer prepared by the condensation of a melt that consists of approximately 90% w/w D-glucose, 10% w/w sorbitol, and 1% w/w citric acid or 0.1% w/w phosphoric acid.

The 1,6 glycosidic linkage predominates in the polymer, but other possible bonds are present. The product contains small quantities of free glucose, sorbitol, and D-anhydroglucoses (levoglucosan), with traces of citric or phosphoric acid.

Polydextrose may be partially reduced by transition-metal catalytic hydrogenation in aqueous solution. It may be neutralized with any food-grade base and/or decolorized and deionized for further purification.

Although not currently included in any pharmacopeias, a specification for polydextrose is contained in the Food Chemicals Codex (FCC). See Table I.

Polydextrose is partially fermented by intestinal microor- ganisms to produce volatile fatty acids. The volatile fatty acids are absorbed in the large intestine. Because of the inefficient way the human body derives energy from volatile fatty acids, polydextrose contributes only one-quarter of the energy of the equivalent weight of sugar, i.e, ≈4 kJ/g (1 kcal/g).(4–6)

When consumed, polydextrose has a negligible effect on blood glucose levels. Polydextrose is metabolized indepen- dently of insulin and contributes only one quarter of the energy of normal carbohydrate.

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

544 Polydextrose

Table I: Food Chemicals Codex specifications for polydextrose.(3)

Test FCC 1996 (Suppl. 2)

Identification +

Heavy metals 45 ppm

5-Hydroxymethylfurfural 40.1%

Lead 40.5 ppm

Molecular weight limit +

Monomers

1,6-Anhydro-D-glucose 44.0%

Glucose and sorbitol 46.0% pH of a 10% solution

Flood MT, Auerbach MH, Craig SA. A review of the clinical toleration studies of polydextrose in food. Food Chem Toxicol 2004; 42(9): 1531–1542.

Burdock GA, Flamm WG. A review of the studies of the safety of polydextrose in food. Food Chem Toxicol 1999; 37(2–3): 233–

264.

Committee on Food Chemicals Codex. Food Chemicals Codex, 4th edn. Washington, DC: National Academy Press, 1996: 297– 300.

Figdor SK, Rennhard HH. Caloric utilization and disposition of [14C]polydextrose in the rat. J Agric Food Chem 1981; 29: 1181– 1189.

Juhr N, Franke J. A method for estimating the available energy of incompletely digested carbohydrates in rats. J Nutr 1992; 122: 1425–1433.

Achour L, Flourie B, Briet F, et al. Gastrointestinal effects and energy value of polydextrose in healthy non-obese men. Am J Clin Nutr 1994; 59: 1362–1368.

General References

Allingham RP. Chemistry of Foods and Beverages: Recent Develop- ments. New York: Academic Press, 1982: 293–303.

Murphy O. Non-polyol low-digestible carbohydrates: food applica- tions and functional benefits. Br J Nutr 2001; 85 (Suppl. 1): S47– S53.

Slade L, Levine H. Glass transitions and water–food interaction. Advances in Food and Nutrition Research. San Diego: Academic Press, 1994.

Macrogol 20000 PhEur: Macrogola USPNF: Polyethylene glycol

Synonyms

Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; PEG; Pluriol E; polyoxyethylene glycol.

Chemical Name and CAS Registry Number

a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl) [25322-68-3]

Empirical Formula and Molecular Weight

HOCH2(CH2OCH2)mCH2OH where m represents the average number of oxyethylene groups.

Alternatively, the general formula H(OCH2CH2)nOH may be used to represent polyethylene glycol, where n is a number m in the previous formula + 1.

See Table I for the average molecular weights of typical polyethylene glycols. Note that the number that follows PEG indicates the average molecular weight of the polymer.

Table I: Structural formula and molecular weight of typical polyethylene glycol polymers.

Grade m Average molecular weight

PEG 200 4.2 190–210

PEG 300 6.4 285–315

PEG 400 8.7 380–420

PEG 540 (blend) — 500–600

PEG 600 13.2 570–613

PEG 900 15.3 855–900

PEG 1000 22.3 950–1 050

PEG 1450 32.5 1 300–1 600

PEG 1540 28.0–36.0 1 300–1 600

PEG 2000 40.0–50.0 1 800–2 200

PEG 3000 60.0–75.0 2 700–3 300

PEG 3350 75.7 3 000–3 700

PEG 4000 69.0–84.0 3 000–4 800

PEG 4600 104.1 4 400–4 800

PEG 8000 181.4 7 000–9 000

Structural Formula

Functional Category

Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Polyethylene glycols (PEGs) are widely used in a variety of pharmaceutical formulations including parenteral, topical, ophthalmic, oral, and rectal preparations. It has been used experimentally in biodegradable polymeric matrices used in controlled-release systems.(1)

Polyethylene glycols are stable, hydrophilic substances that are essentially nonirritant to the skin; see Section 14. They do not readily penetrate the skin, although the polyethylene glycols are water-soluble and are easily removed from the skin by washing, making them useful as ointment bases.(2) Solid grades are generally employed in topical ointments, with the consis- tency of the base being adjusted by the addition of liquid grades of polyethylene glycol.

Mixtures of polyethylene glycols can be used as suppository bases,(3) for which they have many advantages over fats. For example, the melting point of the suppository can be made higher to withstand exposure to warmer climates; release of the drug is not dependent upon melting point; the physical stability on storage is better; and suppositories are readily miscible with rectal fluids. Polyethylene glycols have the following disadvan- tages: they are chemically more reactive than fats; greater care is needed in processing to avoid inelegant contraction holes in the suppositories; the rate of release of water-soluble medications decreases with the increasing molecular weight of the poly- ethylene glycol; and polyethylene glycols tend to be more irritating to mucous membranes than fats.

Aqueous polyethylene glycol solutions can be used either as suspending agents or to adjust the viscosity and consistency of other suspending vehicles. When used in conjunction with other emulsifiers, polyethylene glycols can act as emulsion stabilizers. Liquid polyethylene glycols are used as water-miscible solvents for the contents of soft gelatin capsules. However, they may cause hardening of the capsule shell by preferential

absorption of moisture from gelatin in the shell.

In concentrations up to approximately 30% v/v, PEG 300 and PEG 400 have been used as the vehicle for parenteral dosage forms.

In solid-dosage formulations, higher-molecular-weight poly- ethylene glycols can enhance the effectiveness of tablet binders and impart plasticity to granules.(4) However, they have only limited binding action when used alone, and can prolong disintegration if present in concentrations greater than 5%

546 Polyethylene Glycol

w/w. When used for thermoplastic granulations,(5–7) a mixture of the powdered constituents with 10–15% w/w PEG 6000 is heated to 70–758C. The mass becomes pastelike and forms granules if stirred while cooling. This technique is useful for the preparation of dosage forms such as lozenges when prolonged disintegration is required.

Polyethylene glycols can also be used to enhance the aqueous solubility or dissolution characteristics of poorly soluble compounds by making solid dispersions with an appropriate polyethylene glycol.(8) Animal studies have also been performed using polyethylene glycols as solvents for steroids in osmotic pumps.

In film coatings, solid grades of polyethylene glycol can be used alone for the film-coating of tablets or can be useful as hydrophilic polishing materials. Solid grades are also widely used as plasticizers in conjunction with film-forming poly- mers.(9) The presence of polyethylene glycols in film coats, especially of liquid grades, tends to increase their water permeability and may reduce protection against low pH in enteric-coating films. Polyethylene glycols are useful as plasticizers in microencapsulated products to avoid rupture of the coating film when the microcapsules are compressed into tablets.

Polyethylene glycol grades with molecular weights of 6000 and above can be used as lubricants, particularly for soluble tablets. The lubricant action is not as good as that of magnesium stearate, and stickiness may develop if the material becomes too warm during compression. An antiadherent effect is also exerted, again subject to the avoidance of overheating.

Polyethylene glycols have been used in the preparation of urethane hydrogels, which are used as controlled-release agents. It has also been used in insulin-loaded microparticles for the oral delivery of insulin;(10,11) it has been used in inhalation preparations to improve aerosolization;(12) poly- ethylene glycol nanoparticles have been used to improve the oral bioavailability of cyclosporine;(13) it has been used in self- assembled polymeric nanoparticles as a drug carrier;(14) and copolymer networks of polyethylene glycol grafted with poly(methacrylic acid) have been used as bioadhesive con- trolled drug delivery formulations.(15)

Description

The USPNF 23 describes polyethylene glycol as being an addition polymer of ethylene oxide and water. Polyethylene glycol grades 200–600 are liquids; grades 1000 and above are solids at ambient temperatures.

Liquid grades (PEG 200–600) occur as clear, colorless or slightly yellow-colored, viscous liquids. They have a slight but characteristic odor and a bitter, slightly burning taste. PEG 600 can occur as a solid at ambient temperatures.

Solid grades (PEG>1000) are white or off-white in color, and range in consistency from pastes to waxy flakes. They have a faint, sweet odor. Grades of PEG 6000 and above are

available as free-flowing milled powders.

Pharmacopeial Specifications

See Table II.

Typical Properties

Density:

1.11–1.14 g/cm3 at 258C for liquid PEGs;

1.15–1.21 g/cm3 at 258C for solid PEGs.

<—658C PEG 200 sets to a glass;

—15 to —88C for PEG 300;

4–88C for PEG 400;

15–258C for PEG 600.

Melting point:

37–408C for PEG 1000;

44–488C for PEG 1500;

40–488C for PEG 1540;

45–508C for PEG 2000;

48–548C for PEG 3000;

50–588C for PEG 4000;

55–638C for PEG 6000;

60–638C for PEG 8000;

60–638C for PEG 20000.

Moisture content: liquid polyethylene glycols are very hygro- scopic, although hygroscopicity decreases with increasing molecular weight. Solid grades, e.g. PEG 4000 and above, are not hygroscopic. See Figures 1, 2 and 3.

Particle size distribution: see Figures 4 and 5.

Refractive index:

n25 = 1.459 for PEG 200;

n25 = 1.463 for PEG 300;

n25 = 1.465 for PEG 400;

n25 = 1.467 for PEG 600.

Solubility: all grades of polyethylene glycol are soluble in water and miscible in all proportions with other polyethylene glycols (after melting, if necessary). Aqueous solutions of higher-molecular-weight grades may form gels. Liquid polyethylene glycols are soluble in acetone, alcohols, benzene, glycerin, and glycols. Solid polyethylene glycols are soluble in acetone, dichloromethane, ethanol (95%),

Table II: Pharmacopeial specifications for polyethylene glycol.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + —

Characters — + —

Acidity or alkalinity — + —

Appearance of solution — + +

Density — See Table IV —

Freezing point See Table III See Table IV —

Viscosity — See Table IV See Table V Average molecular weight See Table III — See Table V pH (5% w/v solution) See Table III — 4.5–7.5 Hydroxyl value — See Table IV — Reducing substances — + —

Residue on ignition See Table III — 40.1% Sulfated ash — 40.2% —

Limit of ethylene glycol and 40.25% 40.4% 40.25% diethylene glycol

Ethylene oxide — 41 ppm 410 mg/g

1,4-Dioxane — 410 ppm 410 mg/g

Heavy metals — 420 ppm 45 mg/g

Organic volatile impurities — — +

Water 41.0% 42.0% —

Formaldehyde — 415 ppm —

Polyethylene Glycol 547

Table III: Specifications from JP 2001.

Incompatibilities

Type of PEG

Average molecular weight

The chemical reactivity of polyethylene glycols is mainly confined to the two terminal hydroxyl groups, which can be either esterified or etherified. However, all grades can exhibit some oxidizing activity owing to the presence of peroxide

400 380–420 4–8 4.0–7.0 40.1%

1500 — 37–41 4.0–7.0 40.1%

4000 2 600–3 800 53–57 4.0–7.5 40.25%

6000 7 300–9 300 56–61 4.5–7.5 40.25%

20000 15 000–25 000 56–64 4.5–7.5 40.25%

and methanol; they are slightly soluble in aliphatic hydro- carbons and ether, but insoluble in fats, fixed oils, and mineral oil.

Surface tension: approximately 44 mN/m (44 dynes/cm) for liquid polyethylene glycols; approximately 55 mN/m (55 dynes/cm) for 10% w/v aqueous solution of solid polyethylene glycol.

Viscosity (kinematic): see Tables IV, V, and VI.

Stability and Storage Conditions

Polyethylene glycols are chemically stable in air and in solution, although grades with a molecular weight less than 2000 are hygroscopic. Polyethylene glycols do not support microbial growth, and they do not become rancid.

Polyethylene glycols and aqueous polyethylene glycol solutions can be sterilized by autoclaving, filtration, or gamma irradiation.(16) Sterilization of solid grades by dry heat at 1508C for 1 hour may induce oxidation, darkening, and the formation of acidic degradation products. Ideally, sterilization should be carried out in an inert atmosphere. Oxidation of polyethylene glycols may also be inhibited by the inclusion of a suitable antioxidant.

If heated tanks are used to maintain normally solid polyethylene glycols in a molten state, care must be taken to avoid contamination with iron, which can lead to discolora- tion. The temperature must be kept to the minimum necessary to ensure fluidity; oxidation may occur if polyethylene glycols are exposed for long periods to temperatures exceeding 508C. However, storage under nitrogen reduces the possibility of oxidation.

Polyethylene glycols should be stored in well-closed contain- ers in a cool, dry place. Stainless steel, aluminum, glass, or lined steel containers are preferred for the storage of liquid grades.

impurities and secondary products formed by autoxidation.

Liquid and solid polyethylene glycol grades may be incompatible with some coloring agents.

The antibacterial activity of certain antibiotics is reduced in polyethylene glycol bases, particularly that of penicillin and bacitracin. The preservative efficacy of the parabens may also be impaired owing to binding with polyethylene glycols.

Physical effects caused by polyethylene glycol bases include softening and liquefaction in mixtures with phenol, tannic acid, and salicylic acid. Discoloration of sulfonamides and dithranol can also occur and sorbitol may be precipitated from mixtures. Plastics, such as polyethylene, phenolformaldehyde, polyvinyl chloride, and cellulose-ester membranes (in filters) may be softened or dissolved by polyethylene glycols. Migration of polyethylene glycol can occur from tablet film coatings, leading to interaction with core components.

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