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Incompatibilities

Polyoxyethylene stearates are unstable in hot alkaline solutions owing to hydrolysis, and will also saponify with strong acids or bases. Discoloration or precipitation can occur with salicylates, phenolic substances, iodine salts, and salts of bismuth, silver, and tannins.(2–4) Complex formation with preservatives may also occur.(5) The antimicrobial activity of some materials such as bacitracin, chloramphenicol, phenoxymethylpenicillin, sodium penicillin, and tetracycline may be reduced in the presence of polyoxyethylene stearate concentrations greater than 5% w/w.(6,7)

Method of Manufacture

Polyoxyethylene stearates are prepared by the direct reaction of fatty acids, particularly stearic acid, with ethylene oxide.

certain materials, particularly polyoxyl 40 stearate, have also been used in intravenous injections and oral preparations.(1,4) Polyoxyethylene stearates have been tested extensively for toxicity in animals(8–13) and are widely used in pharmaceutical formulations and cosmetics. They are generally regarded as

essentially nontoxic and nonirritant materials.

Polyoxyl 8 stearate:

LD50 (hamster, oral): 27 g/kg LD50 (rat, oral): 64 g/kg

Polyoxyl 20 stearate:

LD50 (mouse, IP): 0.2 g/kg LD50 (mouse, IV): 0.87 g/kg

Handling Precautions

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

Polyoxyethylene stearates that contain greater than 100 ppm of free ethylene oxide may present an explosion hazard when stored in a closed container. This is due to the release of ethylene oxide into the container headspace, where it can accumulate and so exceed the explosion limit.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (dental solutions; IV injections; ophthalmic preparations; oral capsules and tablets; otic suspensions; topical creams, emulsions, lotions, ointments, and solutions; and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Polyethylene glycol; stearic acid.

Comments

—

Table VII: Typical properties of polyoxyethylene stearates.

Name Acid value Free ethylene oxide HLB value Hydroxyl value Iodine number Melting point (8C) Saponification value Water content (%)

Polyoxyl 6 stearate 45.0 4100 ppm 9.7 — 40.5 28–32 95–110 —

Polyoxyl 8 stearate 42.0 4100 ppm 11.1 87–105 41.0 28–33 82–95 43.0

Polyoxyl 12 stearate 48.5 4100 ppm 13.6 55–75 41.0 ≈ 37 62–78 41.0

Polyoxyl 20 stearate 41.0 4100 ppm 14 50–62 41.0 ≈ 28 46–56 41.0

Polyoxyl 30 stearate 42.0 — 16 35–50 — — 30–45 43.0

Polyoxyl 40 stearate 41.0 — 16.9 27–40 — ≈ 38 25–35 43.0

Polyoxyl 50 stearate 42.0 — 17.9 23–35 — ≈ 42 20–28 43.0

Polyoxyl 100 stearate 41.0 4100 ppm 18.8 15–30 — ≈ 46 9–20 43.0

Polyoxyl 8 distearate 410.0 — — 415 40.5 ≈ 36 115–124 —

Polyoxyl 12 distearate 410.0 4100 ppm 10.6 420 41.0 ≈ 39 93–102 41.0

Polyoxyl 32 distearate 410.0 4100 ppm 14.8 420 40.25 ≈ 45 50–62 41.0

Polyoxyl 150 distearate 7–9 4100 ppm 18.4 415 40.1 53–57 14–20 41.0

588 Polyoxyethylene Stearates

Specific References

Cohn I, Singleton S, Hartwig QL, Atik M. New intravenous fat emulsion. J Am Med Assoc 1963; 183: 755–757.

Thoma K, Ullmann E, Fickel O. The antibacterial activity of phenols in the presence of polyoxyethylene stearates and polyethylene glycols [in German]. Arch Pharm 1970; 303: 289–

296.

Thoma K, Ullmann E, Fickel O. Dimensions and cause of the reaction between phenols and polyoxyethylene stearates [in German]. Arch Pharm 1970; 303: 297–304.

Duchene D, Djiane A, Puisieux F. Tablet study III: influence of nonionic surfactants with ester linkage on the quality of sulfanilamide grains and tablets [in French]. Ann Pharm Fr 1970; 28: 289–298.

Chakravarty D, Lach JL, Blaug SM. Study of complex formation between polyoxyl 40 stearate and some pharmaceuticals. Drug Standards 1957; 25: 137–140.

Ullmann E, Moser B. Effect of polyoxyethylene stearates on the antibacterial activity of antibiotics [in German]. Arch Pharm 1962; 295: 136–143.

Thoma K, Ullmann E, Zelfel G. Investigation of the stability of penicillin G sodium in the presence of nonionic surface active agents (polyethylene glycol derivatives) [in German]. Arch Pharm 1962; 295: 670–678.

Culver PJ, Wilcox CS, Jones CM, Rose RS. Intermediary metabolism of certain polyoxyethylene derivatives in man I: recovery of the polyoxyethylene moiety from urine and feces following ingestion of polyoxyethylene (20) sorbitan monooleate and of polyoxyethylene (40) mono-stearate. J Pharmacol Exp Ther 1951; 103: 377–381.

Oser BL, Oser M. Nutritional studies on rats on diets containing high levels of partial ester emulsifiers I: general plan and

procedures; growth and food utilization. J Nutr 1956; 60: 367– 390.

Oser BL, Oser M. Nutritional studies on rats on diets containing high levels of partial ester emulsifiers II: reproduction and lactation. J Nutr 1956; 60: 489–505.

Oser BL, Oser M. Nutritional studies on rats on diets containing high levels of partial ester emulsifiers III: clinical and metabolic observations. J Nutr 1957; 61: 149–166.

Oser BL, Oser M. Nutritional studies on rats on diets containing high levels of partial ester emulsifiers IV: mortality and post- mortem pathology; general conclusions. J Nutr 1957; 61: 235–

252.

Fitzhugh OG, Bourke AR, Nelson AA, Frawley JP. Chronic oral toxicities of four stearic acid emulsifiers. Toxicol Appl Pharmacol 1959; 1: 315–331.

General References

Satkowski WB, Huang SK, Liss RL. Polyoxyethylene esters of fatty acids. In: Schick MJ, ed. Nonionic Surfactants. New York: Marcel Dekker, 1967: 142–174.

Polyvinyl Acetate Phthalate

Nonproprietary Names

USPNF: Polyvinyl acetate phthalate

Synonyms

Phthalavin; PVAP; Opaseal; Sureteric.

Chemical Name and CAS Registry Number

Polyvinyl acetate phthalate [34481-48-6]

Empirical Formula and Molecular Weight

The USPNF 23 describes polyvinyl acetate phthalate as a reaction product of phthalic anhydride and a partially hydrolyzed polyvinyl acetate. It contains not less than 55.0% and not more than 62.0% of phthalyl (o-carboxybenzoyl, C8H5O3) groups, calculated on an anhydrous acid-free basis.

It has been reported that the free phthalic acid content is dependent on the source of the material.(1)

Structural Formula

Plasticizers are often included in polyvinyl acetate phthalate coating formulations to enable a continuous, homogeneous, noncracking film to be produced. Polyvinyl acetate phthalate has been shown to be compatible with several plasticizers such as glyceryl triacetate, triethyl citrate, acetyl triethylcitrate, diethyl phthalate and polyethylene glycol 400.

For enteric coating applications, polyvinyl acetate phthalate is dissolved in a solvent system together with other additives such as diethyl phthalate and stearic acid. Methanol may be used as the solvent if a colorless film is required; for a colored film, methanol or ethanol/water may be used depending on the amount of pigment to be incorporated. A weight increase of up to 8% is necessary for nonpigmented systems, whereas for pigmented systems a weight increase of 6% is usually required. A formulated, aqueous-based coating solution (Sureteric, Colorcon) is available commercially for the enteric coating of tablets, hard and soft gelatin capsules and granules.

Polyvinyl acetate phthalate has superseded materials such as shellac in producing the initial layers of coating (the sealing coat) in the sugar coating process for tablets. The sealing coating should be kept as thin as possible while providing an adequate barrier to moisture, a balance that is often difficult to achieve in practice. A solvent system containing a high proportion of industrial methylated spirits and other additives can be used. Two coats are usually sufficient to seal most tablets, although up to five may be necessary for tablets containing alkaline ingredients. If an enteric coating is also required, between six and 12 coats may be necessary, see Table I.

The properties of polyvinyl acetate phthalate enteric coating have been compared with those of other enteric polymers such as cellulose acetate phthalate(2,3) and Eudragit L 30D.(3) The factors that affect the release kinetics from polyvinyl acetate phthalate enteric-coated tablets have also been described.(4) A method for enteric coating hypromellose capsules which avoids the sealing step prior to coating has been developed. The properties of several enteric coating polymers, including polyvinyl acetate phthalate, were assessed.(5)

Depending on the phthalyl content, a will vary with b in mole percent. The acetyl content c remains constant depending on the starting material.

Functional Category

Coating agent.

Applications in Pharmaceutical Formulation or Technology

Polyvinyl acetate phthalate is a viscosity-modifying agent that is used in pharmaceutical formulations to produce enteric coat- ings for products and for the core sealing of tablets prior to a sugar-coating process. Polyvinyl acetate phthalate does not exhibit tackiness during coating and produces strong robust films.

Table I: Uses of polyvinyl acetate phthalate.

Use Concentration (%)

Tablet enteric film coating 9–10

Tablet sealant (sugar-coating) 28–29

Description

Polyvinyl acetate phthalate is a free-flowing white to off-white powder and may have a slight odor of acetic acid. The material is essentially amorphous.(6)

Pharmacopeial Specifications

See Table II.

590 Polyvinyl Acetate Phthalate

Table II: Pharmacopeial specifications for polyvinyl acetate phthalate.

Test USPNF 23

Identification +

Apparent viscosity at 258C 7–11 mPa s

Water 45.0%

Residue on ignition 41.0%

Free phthalic acid 40.6%

Free acid other than phthalic 40.6%

Organic volatile impurities +

Phthalyl content 55.0–62.0%

Typical Properties

The characteristics of polyvinyl acetate phthalate from two sources have been compared; values for molecular weight (60 700; 47 000), moisture content (3.74%; 2.20%) and density (1.31 g/cm3; 1.37 g/cm3) have been reported. The solubility of each polyvinyl acetate phthalate in a range of different solvents was described and scanning electron photo- micrographs were produced to give evidence of the different polymer morphology.(7)

Glass transition temperature: a glass transition temperature of

42.58C has been reported for polyvinyl acetate phthalate; the glass transition temperature was shown to fall with the addition of increasing amounts of the plasticizer diethyl phthalate.(6)

Solubility: soluble in ethanol and methanol; sparingly soluble in acetone and propan-2-ol; practically insoluble in chloro- form, dichloromethane, and water. In buffer solutions, polyvinyl acetate phthalate (200 mg/L) is insoluble below pH 5 and becomes soluble at pH values above 5. Polyvinyl acetate pththalate shows a sharp solubility response with pH; this occurs at pH 4.5–5.0, which is lower than for most other polymers used for enteric coatings. Solubility is also influenced by ionic strength. See Table III.

Table III: Solubility of polyvinyl acetate phthalate.

Solvent Solubility at 258C

Acetone/ethanol (1 : 1 w/w) 1 in 3

Acetone/methanol (1 : 1 w/w) 1 in 4

Ethanol (95%) 1 in 4

Methanol 1 in 2

Methanol/dichloromethane (1 : 1 w/w) 1 in 3

Viscosity (dynamic): the viscosity of a solution of polyvinyl acetate phthalate:methanol (1 : 1) is 5000 mPa s. In metha- nol/dichloromethane systems, viscosity increases as the concentration of methanol in the system increases.

Stability and Storage Conditions

Polyvinyl acetate phthalate should be stored in airtight containers. It is relatively stable to temperature and humidity and does not age, giving predictable release profiles even after prolonged storage.

At high temperature and humidity, polyvinyl acetate phthalate undergoes less hydrolysis than other commonly used enteric coating polymers. In aqueous colloidal dispersions of polyvinyl acetate phthalate, the formation of free phthalic

acid through hydrolysis was found to adversely affect physical stability.(1)

Following storage at room temperature for 9 months, capsules coated with a commercial polyvinyl acetate phthalate formulation (Coateric) were found to retain gastroresistant properties and showed no apparent physical change; however, a delayed drug dissolution profile was observed after storage. Storage at 378C, or 378C and 80% relative humidity, for 3 months resulted in capsules having an unsatisfactory appear- ance.(3)

Incompatibilities

Polyvinyl acetate phthalate reacts with povidone to form an insoluble complex that precipitates out of solution;(8) benzo- caine is also incompatible with polyvinyl acetate phthalate.(9) Erythromycin disperses in polyvinyl acetate phthalate and has been shown to be physically stable(10) while omeprazole exists in the amorphous form in polyvinyl acetate phthalate coatings with no evidence of interaction.(11)

Method of Manufacture

Polyvinyl acetate phthalate is a reaction product of phthalic anhydride, sodium acetate, and a partially hydrolyzed poly- vinyl alcohol. The polyvinyl alcohol is a low molecular weight grade, and 87–89 mole percent is hydrolyzed. Therefore, the polyvinyl acetate phthalate polymer is a partial esterification of a partially hydrolyzed polyvinyl acetate.

See also Section 4.

Safety

Polyvinyl acetate phthalate is used in oral pharmaceutical formulations and is generally regarded as an essentially nonirritant and nontoxic material when used as an excipient.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Gloves and eye protection are recommended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (sustained- action oral tablet). Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Cellulose acetate phthalate; hypromellose phthalate; poly- methacrylates; shellac.

Comments

Polyvinyl acetate phthalate dissolves along the whole length of the duodenum.

Specific References

Davis MB. Preparation and stability of aqueous-based enteric polymer dispersions. Drug Dev Ind Pharm 1986; 12(10): 1419–

1448.

Polyvinyl Acetate Phthalate 591

Porter SC, Ridgway K. The permeability of enteric coatings and the dissolution rates of coated tablets. J Pharm Pharmacol 1982; 34: 5–8.

Murthy KS, Enders NA, Mahjour M, Fawzi MB. A comparative evaluation of aqueous enteric polymers in capsule coatings. Pharm Technol 1986; 10(10): 36, 38, 40, 42, 44.

Ozturk SS, Palsson BO, Donohoe B, Dressman JB. Kinetics of release from enteric-coated tablets. Pharm Res 1988; 5(9): 550–

565.

Huyghebaert N, Vermeire A, Remon JP. Alternative method for enteric coating of HPMC capsules resulting in ready-to-use enteric- coated capsules. Eur J Pharm Sci 2004; 21(5): 617–623.

Porter SC, Ridgway K. An evaluation of the properties of enteric coating polymers: measurement of glass transition temperature. J Pharm Pharmacol 1983; 35: 341–344.

Nesbitt RU, Goodhart FW, Gordon RH. Evaluation of polyvinyl acetate phthalate as an enteric coating material. Int J Pharm 1985; 26: 215–226.

Kumar V, Yang T, Yang Y. Interpolymer complexation I: preparation and characterization of a polyvinyl acetate phtha- late–polyvinylpyrrolidone (PVAP-PVP) complex. Int J Pharm 1999; 188: 221–232.

Kumar V, Banker GS. Incompatibility of polyvinyl acetate phthalate with benzocaine: isolation and characterization of 4- phthalimidobenzoic acid ethyl ester. Int J Pharm 1992; 79: 61–65.

Sarisuta N, Kumpugdee M, Mu¨ ller BW, Puttipipatkhachorn S. Physico-chemical characterization of interactions between erythromycin and various film polymers. Int J Pharm 1999; 186: 109–118.

Sarisuta N, Kumpugdee M. Crystallinity of omeprazole in various film polymers. Pharm Pharmacol Commun 2000; 6: 7–11.

PhEur: Poly(vinylis acetas) USP: Polyvinyl alcohol

Synonyms

Airvol; Alcotex; Elvanol; Gelvatol; Gohsenol; Lemol; Mowiol; Polyvinol; PVA; vinyl alcohol polymer.

Chemical Name and CAS Registry Number

Ethenol, homopolymer [9002-89-5]

Empirical Formula and Molecular Weight

(C2H4O)n 20 000–200 000

Polyvinyl alcohol is a water-soluble synthetic polymer represented by the formula (C2H4O)n. The value of n for commercially available materials lies between 500 and 5000, equivalent to a molecular weight range of approximately 20 000–200 000, see Table I.

Table I: Commercially available grades of polyvinyl acohol.

Grade Molecular weight

High viscosity ~200 000

Medium viscosity ~130 000

Low viscosity ~20 000

Structural Formula

Functional Category

Coating agent; lubricant; stabilizing agent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Polyvinyl alcohol is used primarily in topical pharmaceutical and ophthalmic formulations; see Table II.(1–3) It is used as a stabilizing agent for emulsions (0.25–3.0% w/v). Polyvinyl alcohol is also used as a viscosity-increasing agent for viscous formulations such as ophthalmic products. It is used in artificial tears and contact lens solutions for lubrication purposes, in sustained-release formulations for oral administration,(4) and in transdermal patches.(5) Polyvinyl alcohol may be made into microspheres when mixed with a glutaraldehyde solution.(6)

Table II: Uses of polyvinyl alcohol.

Use Concentration (%)

Emulsions 0.5

Ophthalmic formulations 0.25–3.00

Topical lotions 2.5

Description

Polyvinyl alcohol occurs as an odorless, white to cream-colored granular powder.

Pharmacopeial Specifications

See Table III.

Table III: Pharmacopeial specifications for polyvinyl alcohol.

Test PhEur 2005 USP 28

Viscosity — +

pH 4.5–6.5 5.0–8.0

Loss on drying 45.0% 45.0%

Residue on ignition 41.0% 42.0%

Water-soluble substances — 40.1%

Degree of hydrolysis — 40.1%

Organic volatile impurities — +

Assay — 85.0–115.0%

Typical Properties

Melting point:

2288C for fully hydrolyzed grades; 180–1908C for partially hydrolyzed grades.

Refractive index: n25 = 1.49–1.53

Solubility: soluble in water; slightly soluble in ethanol (95%); insoluble in organic solvents. Dissolution requires disper- sion (wetting) of the solid in water at room temperature followed by heating the mixture to about 908C for approximately 5 minutes. Mixing should be continued while the heated solution is cooled to room temperature.

Specific gravity:

1.19–1.31 for solid at 258C;

1.02 for 10% w/v aqueous solution at 258C.

Specific heat: 1.67 J/g (0.4 cal/g)

Viscosity (dynamic): see Table IV.

Table IV: Viscosity of commercial grades of polyvinyl alcohol.

Grade Dynamic viscosity of 4% w/v aqueous solution at 208C (mPa s)

High viscosity 40.0–65.0

Medium viscosity 21.0–33.0

Low viscosity 4.0–7.0

Polyvinyl Alcohol 593

Stability and Storage Conditions

Polyvinyl alcohol is stable when stored in a tightly sealed container in a cool, dry place. Aqueous solutions are stable in corrosion-resistant sealed containers. Preservatives may be added to the solution if extended storage is required. Polyvinyl alcohol undergoes slow degradation at 1008C and rapid degradation at 2008C; it is stable on exposure to light.

Incompatibilities

Polyvinyl alcohol undergoes reactions typical of a compound with secondary hydroxy groups, such as esterification. It decomposes in strong acids, and softens or dissolves in weak acids and alkalis. It is incompatible at high concentration with inorganic salts, especially sulfates and phosphates; precipita- tion of polyvinyl alcohol 5% w/v can be caused by phosphates. Gelling of polyvinyl alcohol solution may occur if borax is present.

Method of Manufacture

Polyvinyl alcohol is produced through the hydrolysis of polyvinyl acetate. The repeating unit of vinyl alcohol is not used as the starting material because it cannot be obtained in the quantities and purity required for polymerization purposes. The hydrolysis proceeds rapidly in methanol, ethanol, or a mixture of alcohol and methyl acetate, using alkalis or mineral acids as catalysts.

Safety

Polyvinyl alcohol is generally considered a nontoxic material. It is nonirritant to the skin and eyes at concentrations up to 10%; concentrations up to 7% are used in cosmetics.

Studies in rats have shown that polyvinyl alcohol 5% w/v aqueous solution injected subcutaneously can cause anemia and infiltrate various organs and tissues.(7)

LD50 (mouse, oral): 14.7 g/kg LD50 (rat, oral): >20 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Polyvinyl alcohol dust may be an irritant on inhalation. Handle in a well-ventilated environment.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (ophthalmic preparations and oral tablets). Included in nonparenteral

medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

—

Comments

Various grades of polyvinyl alcohol are commercially available. The degree of polymerization and the degree of hydrolysis are the two determinants of their physical properties. Pharmaceu- tical grades are partially hydrolyzed materials and are named according to a coding system. The first number following a trade name refers to the degree of hydrolysis and the second set of numbers indicates the approximate viscosity (dynamic), in mPa s, of a 4% w/v aqueous solution at 208C.

Specific References

Krishna N, Brow F. Polyvinyl alcohol as an ophthalmic vehicle: effect on regeneration of corneal epithelium. Am J Ophthalmol 1964; 57: 99–106.

Patton TF, Robinson JR. Ocular evaluation of polyvinyl alcohol vehicle in rabbits. J Pharm Sci 1975; 64: 1312–1316.

Anonymous. New method of ocular drug delivery launched.

Pharm J 1993; 250: 174.

Carstensen JT, Marty JP, Puisieux F, Fessi H. Bonding mechanisms and hysteresis areas in compression cycle plots. J Pharm Sci 1981; 70: 222–223.

Wan LSC, Lim LY. Drug release from heat-treated polyvinyl alcohol films. Drug Dev Ind Pharm 1992; 18: 1895–1906.

Thanoo BC, Sunny MC, Jayakrishnan A. Controlled release of oral drugs from crosslinked polyvinyl alcohol microspheres. J Pharm Pharmacol 1993; 45: 16–20.

Hall CE, Hall O. Polyvinyl alcohol: relationship of physicochem- ical properties to hypertension and other pathophysiologic sequelae. Lab Invest 1963; 12: 721–736.

General References

Chudzikowski R. Polyvinyl alcohol. Manuf Chem Aerosol News 1970;

41(7): 31–37.

Finch CA, ed. Polyvinyl Alcohol Developments. Chichester: Wiley, 1992.

Alginic acid, potassium salt; E402; Improved Kelmar; potas- sium polymannuronate.

Chemical Name and CAS Registry Number

Potassium alginate [9005-36-1]

Empirical Formula and Molecular Weight

(C6H7O6K)n

Potassium alginate is the potassium salt of alginic acid, a polyuronide made up of a sequence of two hexuronic acid residues, namely D-mannuronic acid and L-guluronic acid. The two sugars form blocks of up to 20 units along the chain with the proportion of the blocks dependent on the species of seaweed and also the part of the seaweed used. The number and length of the blocks is important in determining the physical properties of the alginate produced; the number and sequence of the mannuronate and guluronate residues varies in the naturally occurring alginate.

Structural Formula

See Section 4.

Functional Category

Emulsifying agent; stabilizing agent; suspending agent; thicken- ing agent.

Applications in Pharmaceutical Formulation or Technology

Potassium alginate is widely used in foods as a stabilizer, thickener, and emulsifier; however, its use as a pharmaceutical excipient is currently limited to experimental hydrogel systems. The viscosity, adhesiveness, elasticity, stiffness, and cohesive- ness of potassium alginate hydrogels has been determined and compared with values from a range of other hydrogel-forming materials.(1) The effect of calcium ions on the rheological properties of procyanidin hydrogels containing potassium alginate and intended for oral administration has also been investigated.(2)

Description

Potassium alginate occurs as a white to yellowish, fibrous or granular powder; it is almost odorless and tasteless.

Pharmacopeial Specifications

See Section 18.

Typical Properties

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