med 11

Acetic acid is usually made by one of three routes: acetaldehyde oxidation, involving direct air or oxygen oxidation of liquid acetaldehyde in the presence of manganese acetate, cobalt acetate, or copper acetate; liquid-phase oxidation of butane or naphtha; methanol carbonylation using a variety of techniques.

Safety

Acetic acid is widely used in pharmaceutical applications primarily to adjust the pH of formulations and is thus generally regarded as relatively nontoxic and nonirritant. However, glacial acetic acid or solutions containing over 50% w/w acetic acid in water or organic solvents are considered corrosive and can cause damage to skin, eyes, nose, and mouth. If swallowed glacial acetic acid causes severe gastric irritation similar to that caused by hydrochloric acid.(1)

Acetic Acid, Glacial 7

Dilute acetic acid solutions containing up to 10% w/w of acetic acid have been used topically following jellyfish stings.(2) Dilute acetic acid solutions containing up to 5% w/w of acetic acid have also been applied topically to treat wounds and burns infected with Pseudomonas aeruginosa.(3)

The lowest lethal oral dose of glacial acetic acid in humans is reported to be 1470 mg/kg.(4) The lowest lethal concentration on inhalation in humans is reported to be 816 ppm.(4) Humans, are, however, estimated to consume approximately 1 g/day of acetic acid from the diet.

LD50 (mouse, IV): 0.525 g/kg(4) LD50 (rabbit, skin): 1.06 g/kg LD50 (rat, oral): 3.31 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Acetic acid, particularly glacial acetic acid, can cause burns on contact with the skin, eyes, and mucous membranes. Splashes should be washed with copious quantities of water. Protective clothing, gloves, and eye protection are recommended.

In the UK, the occupational exposure limits for acetic acid are 25 mg/m3 (10 ppm) long-term (8-hour TWA) and 37 mg/m3 (15 ppm) short-term (15-minutes).(5)

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (injections, nasal, ophthal- mic, and oral preparations). Included in parenteral and nonparenteral preparations licensed in the UK.

Related Substances

Acetic acid; artificial vinegar; dilute acetic acid.

Acetic acid

Comments: a diluted solution of glacial acetic acid containing 30–37% w/w of acetic acid. See Section 18.

Artificial vinegar

Comments: a solution containing 4% w/w of acetic acid.

Dilute acetic acid

Comments: a weak solution of acetic acid which may contain between 6–10% w/w of acetic acid. See Section 18.

Comments

In addition to glacial acetic acid, many pharmacopeias contain monographs for diluted acetic acid solutions of various strengths. For example, the USPNF 23 has a monograph for acetic acid, which is defined as an acetic acid solution containing 36.0–37.0% w/w of acetic acid. Similarly, the BP 2004 contains separate monographs for glacial acetic acid, acetic acid (33%), and acetic acid (6%). Acetic acid (33%) BP 2004 contains 32.5–33.5% w/w of acetic acid. Acetic acid (6%) BP 2004 contains 5.7–6.3% w/w of acetic acid. The JP 2001 also contains a monograph for acetic acid that specifies that it contains 30.0–32.0% w/w of acetic acid.

A specification for glacial acetic acid is contained in the Food Chemicals Codex (FCC).

The EINECS number for acetic acid is 200-580-7.

Specific References

Sweetman SC, ed. Martindale: The Complete Drug Reference, 34th edn. London: Pharmaceutical Press, 2005: 1645.

Fenner PJ, Williamson JA. Worldwide deaths and severe enveno- mation from jellyfish stings. Med J Aust 1996; 165: 658–661.

Milner SM. Acetic acid to treat Pseudomonas aeruginosa in superficial wounds and burns. Lancet 1992; 340: 61.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

11th edn. New York: Wiley, 2004: 15–16.

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

Table I: Pharmacopeial specifications for acetone.

BP: Acetone PhEur: Acetonum USPNF: Acetone

Dimethylformaldehyde; dimethyl ketone; b-ketopropane; pyro- acetic ether.

Chemical Name and CAS Registry Number

2-Propanone [67-64-1]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Acetone is used as a solvent or cosolvent in topical prepara- tions, and as an aid in wet granulation.(1,2) It has also been used when formulating tablets with water-sensitive active ingredi- ents, or to solvate poorly water-soluble binders in a wet granulation process. Acetone has also been used in the formulation of microspheres to enhance drug release.(3) Owing to its low boiling point, acetone has been used to extract thermolabile substances from crude drugs.(4)

Description

Acetone is a colorless volatile, flammable, transparent liquid, with a sweetish odor and pungent sweetish taste.

Pharmacopeial Specifications

See Table I.

Identification + +

Characters + —

Appearance of solution + —

Acidity or alkalinity + —

Relative density 0.790–0.793 40.789

Related substances + —

Matter insoluble in water + —

Reducing substances + +

Residue on evaporation 450 ppm 40.004% Water 43 g/L +

Assay — 599.0%

Typical Properties

Boiling point: 56.28C Flash point: –208C Melting point: 94.38C

Refractive index: n20 = 1.359

Solubility: soluble in water; freely soluble in ethanol (95%)

Vapor pressure: 185 mmHg at 208C

Stability and Storage Conditions

Acetone should be stored in a cool, dry, well-ventilated place out of direct sunlight.

Incompatibilities

Acetone reacts violently with oxidizing agents, chlorinated solvents, and alkali mixtures. It reacts vigorously with sulfur dichloride, potassium t-butoxide, and hexachloromelamine. Acetone should not be used as a solvent for iodine, as it forms a volatile compound that is extremely irritating to the eyes.(4)

Method of Manufacture

Acetone is obtained by fermentation as a by-product of n-butyl alcohol manufacture, or by chemical synthesis from isopropyl alcohol; from cumene as a by-product in phenol manufacture; or from propane as a by-product of oxidation-cracking.

Safety

Acetone is considered moderately toxic, and is a skin irritant and severe eye irritant. Skin irritation has been reported due to its defatting action, and prolonged inhalation may result in headaches. Inhalation of acetone can produce systemic effects such as conjunctival irritation, respiratory system effects, nausea, and vomiting.(5)

LD50 (mouse, oral): 3.0 g/kg(5) LD50 (mouse, IP): 1.297 g/kg LD50 (rabbit, oral): 5.340 g/kg LD50 (rabbit, skin): 0.2 g/kg

Acetone 9

LD50 (rat, IV): 5.5 g/kg LD50 (rat, oral): 5.8 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Acetone is a skin and eye irritant (see Section 14), therefore gloves, eye protection and a respirator are recommended. In the UK, the long-term (8-hour TWA) exposure limit for acetone is 1210 mg/m3 (500 ppm). The short-term (15-minute) exposure limit is 3620 mg/m3 (1500 ppm).(6)

Regulatory Status

Included in the FDA Inactive Ingredients Guide (inhalation solution; oral tablets; topical preparations). Included in the Canadian List of Acceptable Non-medicinal Ingredients. Included in nonparenteral medicines licensed in the UK.

Related Substances

—

Comments

A specification for acetone is included in the Japanese Pharmaceutical Excipients (JPE).(7) The EINECS number for acetone is 200-662-2.

Specific References

Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd edn. Endicott, NY: Synapse Information Resources, 2002: 282.

Tang ZG, Black RA, Curran JM, et al. Surface properties and biocompatibility of solvent-cast poly[e-caprolactone] films. Bio- materials 2004; 25(19): 4741–4748.

Ruan G, Feng SS. Preparation and characterization of poly(lactic acid)–poly(ethylene glycol)–poly(lactic acid) (PLA-PEG-PLA) microspheres for controlled release of paclitaxel. Biomaterials 2003; 24(27): 5037–5044.

Todd RG, Wade A, eds. The Pharmaceutical Codex, 11th edn. London: Pharmaceutical Press, 1979: 6.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 22–23.

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

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 35–36.

Acetyltributyl Citrate

Nonproprietary Names

USPNF: Acetyltributyl citrate PhEur: Tributylis acetylcitras

Synonyms

Acetylbutyl citrate; acetylcitric

Citroflex A-4; tributyl acetylcitrate; tributyl O-acetylcitrate; tributyl citrate acetate.

Chemical Name and CAS Registry Number

1,2,3-Propanetricarboxylic acid, 2-acetyloxy, tributyl ester [77-90-7]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Acetyltributyl citrate is used to plasticize polymers in for- mulated pharmaceutical coatings,(1–5) including capsules, tablets, beads, and granules for taste masking, immediate release, sustained-release and enteric formulations.

Description

Acetyltributyl citrate is a clear, odorless, practically colorless, oily liquid.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for acetyltributyl citrate.

Test PhEur 2005 USPNF 23

Sulfated ash — 40.10%

Acidity + +

Water 40.25% 40.25%

Heavy metals 40.001% 40.001%

Assay (anhydrous basis) 599.0% 99.0–101.0%

Typical Properties

Acid value: 0.02

Boiling point: 3268C (decomposes)

Flash point: 2048C

Pour point: —598C

Solubility: miscible with acetone, ethanol, and vegetable oil; practically insoluble in water.

Viscosity (dynamic): 33 mPa s (33 cP) at 258C

Stability and Storage Conditions

Acetyltributyl citrate should be stored in a well-closed container in a cool, dry location at temperatures not exceeding 388C. When stored in accordance with these conditions, acetyltributyl citrate is a stable product.

Incompatibilities

Acetyltributyl citrate is incompatible with strong alkalis and oxidizing materials.

Method of Manufacture

Acetyltributyl citrate is prepared by the esterification of citric acid with butanol followed by acylation with acetic anhydride.

Safety

Acetyltributyl citrate is used in oral pharmaceutical formula- tions and films intended for direct food contact. It is also used in self-adhesive thin films used for topical delivery systems.(6) It is generally regarded as a relatively nontoxic and nonirritating material. However, ingestion of large quantities may be harmful.

LD50 (cat, oral): >50 mL/kg(7) LD50 (mouse, IP): >4 g/kg LD50 (rat, oral): >31.5 g/kg

Handling Precautions

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

Acetyltributyl Citrate 11

slightly irritating to the eyes and may be irritating to the respiratory system as a mist or at elevated temperatures. Gloves and eye protection are recommended for normal handling, and a respirator is recommended when using acetyltributyl citrate at elevated temperatures.

Regulatory Status

Included in FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Approved in the USA for direct food contact in food films.

Related Substances

Acetyltriethyl citrate; tributyl citrate; triethyl citrate.

Comments

Acetyltributyl citrate is used as a plasticizer in food contact films, although it has been known to migrate from food-grade PVC films into high-fat foods such as olive oil.(8)

Polylactide plasticized with acetyltributyl citrate has been investigated as a biodegradable barrier for use in guided-tissue regeneration therapy.(9)

The EINECS number for acetyltributyl citrate is 201-067-0.

Specific References

Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizer on the physical and mechanical properties of acrylic resin copolymers. Int J Pharm 1994; 103: 293–301.

Lehmann K. Chemistry and application properties of polymetha- crylate coating systems. In: McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989: 153–245.

Steurnagel CR. Latex emulsions for controlled drug delivery. In: McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989: 1–61.

Gutierrez-Rocca JC, McGinity JW. Influence of aging on the physical-mechanical properties of acrylic resin films cast from aqueous dispersions and organic solutions. Drug Dev Ind Pharm 1993; 19(3): 315–332.

Repka MA, Gerding TG, Repka SL. Influence of plasticisers and drugs on the physical-mechanical properties of hydroxypropylcel- lulose films prepared by hot melt extrusion. Drug Dev Ind Pharm 1999; 25(5): 625–633.

Lieb S, Szeimies RM, Lee G. Self-adhesive thin films for topical delivery of 5-aminolevulinic acid. Eur J Pharm Biopharm 2002; 53(1): 99–106.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

11th edn. New York: Wiley, 2004: 3512.

Goulas AE, Riganakos KA, Ehlermann DA, et al. Effect of high- dose electron beam irradiation on the migration of DOA and ATBC plasticizers from food-grade PVC and PVDC/PVC films, respectively, into olive oil. J Food Prot 1998; 61(6): 720–724.

Dorfer CE, Kim TS, Steinbrenner H, et al. Regenerative period- ontal surgery in interproximal intrabony defects with biodegrad- able barriers. J Clin Peridontol 2000; 27(3): 162–168.

Acetyltriethyl Citrate

Nonproprietary Names

USPNF: Acetyltriethyl citrate

Synonyms

ATEC; Citroflex A-2; triethyl acetylcitrate; triethyl O-acetyl- citrate; triethyl citrate acetate.

Chemical Name and CAS Registry Number

1,2,3-Propanetricarboxylic acid, 2-acetyloxy, triethyl ester [77- 89-4]

Empirical Formula and Molecular Weight

Applications in Pharmaceutical Formulation or Technology

Acetyltriethyl citrate is used to plasticize polymers in formu- lated pharmaceutical coatings.(1) The coating applications include capsules, tablets, beads and granules for taste masking, immediate release, sustained-release and enteric formula- tions.(2–5) It is also used in diffusion-controlled release drug delivery systems.(6)

Description

Acetyltriethyl citrate occurs as a clear, odorless, practically colorless oily liquid.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for acetyltriethyl citrate.

Test USPNF 23

Identification +

Specific gravity 1.135–1.139

Refractive index 1.432–1.441

Acidity +

Water 40.3%

Heavy metals 40.001%

Assay (anhydrous basis) 599.0%

Typical Properties

Acid value: 0.02

Boiling point: 2948C (decomposes)

Flash point: 1888C

Pour point: —438C

Solubility: soluble 1 in 140 of water; miscible with acetone, ethanol, and propan-2-ol.

Viscosity (dynamic): 54 mPa s (54 cP) at 258C.

Stability and Storage Conditions

Acetyltriethyl citrate should be stored in dry, closed containers at temperatures not exceeding 388C. When stored in accor- dance with these conditions, acetyltriethyl citrate is a stable product.

Incompatibilities

Acetyltriethyl citrate is incompatible with strong alkalis and oxidizing materials.

Method of Manufacture

Acetyltriethyl citrate is prepared by the esterification of citric acid with ethanol followed by acylation with acetic anhydride.

Safety

Acetyltriethyl citrate is used in oral pharmaceutical formula- tions and is generally regarded as a nontoxic and nonirritating material. However, ingestion of large quantities may be harmful.

LD50 (cat, oral): 8.5 g/kg(7) LD50 (mouse, IP): 1.15 g/kg LD50 (rat, oral): 7 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Acetyltriethyl citrate may be irritating to the eyes or the respiratory system as a mist or at elevated temperatures. Gloves and eye protection are recom- mended for normal handling and a respirator is recommended if used at elevated temperatures.

Acetyltriethyl Citrate 13

Regulatory Status

Approved in the USA for direct food contact in food films.

Related Substances

Acetyltributyl citrate; tributyl citrate; triethyl citrate.

Comments

The EINECS number for acetyltriethyl citrate is 201-066-5.

Specific References

Jensen JL, Appel LE, Clair JH, Zentner GM. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes. J Pharm Sci 1995; 84: 530–533.

Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizer on the physical and mechanical properties of acrylic resin copolymers. Int J Pharm 1994; 103: 293–301.

Lehmann K. Chemistry and application properties of polymeth- acrylate coating systems. In: McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989: 153–245.

Steurnagel CR. Latex emulsions for controlled drug delivery. In: McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989: 1–61.

Siepmann J, Lecomte F, Bodmeier R. Diffusion-controlled drug delivery systems: calculation of the required composition to achieve desired release profiles. J Control Release 1999; 60(2–3): 379–389.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

11th edn. New York: Wiley, 2004: 58–59.

JP: Agar PhEur: Agar USPNF: Agar

Synonyms

Agar-agar; Bengal isinglass; Ceylon isinglass; Chinese isinglass; E406; gelosa; gelose; Japan agar; Japan isinglass; layor carang.

Chemical Name and CAS Registry Number

Agar [9002-18-0]

Empirical Formula and Molecular Weight

See Section 5.

Structural Formula

Agar is a dried, hydrophilic, colloidal polysaccharide complex extracted from the agarocytes of algae of the Rhodophyceae. The structure is believed to be a complex range of polysacchar- ide chains having alternating a-(1→3) and b-(1→4) linkages. There are three extremes of structure noted: namely neutral agarose; pyruvated agarose having little sulfation; and a sulfated galactan. Agar can be separated into a natural gelling fraction, agarose, and a sulfated nongelling fraction, agaro- pectin.

Functional Category

Emulsifying agent; stabilizing agent; suppository base; suspend- ing agent; sustained-release agent; tablet binder; thickening agent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Agar is widely used in food applications as a stabilizing agent. In pharmaceutical applications, agar is used in a handful of oral tablet and topical formulations. It has also been investigated in a number of experimental pharmaceutical applications includ- ing as a sustained-release agent in gels, beads, microspheres, and tablets.(1–4) It has also been reported to work as a disintegrant in tablets.(5) Agar has been used in a floating controlled-release tablet; the buoyancy in part being attributed to air entrapped in the agar gel network.(6) It can be used as a viscosity-increasing agent in aqueous systems. Agar can also be used as a base for nonmelting, and nondisintegrating suppo- sitories.(7) Agar has an application as a suspending agent in pharmaceutical suspensions.(8)

Description

Agar occurs as transparent, odorless, tasteless strips or as a coarse or fine powder. It may be weak yellowish-orange,

yellowish-gray to pale-yellow colored, or colorless. Agar is tough when damp, brittle when dry.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for agar.

41000/g

(a) Total viable aerobic count, determined by plate-count.

Typical Properties

Solubility: soluble in boiling water to form a viscous solution; practically insoluble in ethanol (95%), and cold water. A 1% w/v aqueous solution forms a stiff jelly on cooling.

Stability and Storage Conditions

Agar solutions are most stable at pH 4–10.

Agar should be stored in a cool, dry, place. Containers of this material may be hazardous when empty since they retain product residues (dust, solids).

Incompatibilities

Agar is incompatible with strong oxidizing agents. Agar is dehydrated and precipitated from solution by ethanol (95%). Tannic acid causes precipitation; electrolytes cause partial dehydration and decrease in viscosity of sols.(9)

Agar 15

Method of Manufacture

Agar is obtained by freeze-drying a mucilage derived from Gelidium amansii Lamouroux, other species of the same family (Gelidiaceae), or other red algae (Rhodophyta).

Safety

Agar is widely used in food applications and has been used in oral and topical pharmaceutical applications. It is generally regarded as relatively nontoxic and nonirritant when used as an excipient.

LD50 (hamster, oral): 6.1 g/kg(10) LD50 (mouse, oral): 16.0 g/kg LD50 (rabbit, oral): 5.8 g/kg LD50 (rat, oral): 11.0 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled. When heated to decomposition, agar emits acrid smoke and fumes.

Regulatory Status

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

Related Substances

—

Comments

The EINECS number for agar is 232-658-1.

Specific References

Bhardwaj TJ, Kanwar M, Lal R, Gupta A. Natural gums and modified natural gums as sustained release carriers. Drug Dev Ind Pharm 2000; 26(10): 1025–1038.

Sakr FM, El-Said Y, El-Helw A. Design and evaluation of a dry solidification technique for preparing pharmaceutical beads. STP Pharma Sci 1995; 5(4): 291–295.

Boraie NA, Naggar VF. Sustained release of theophylline and aminophylline from agar tablets. Acta Pharm Jugosl 1984; 34(Oct–Dec): 247–256.

Nakano M, Nakamura Y, Takikawa K, et al. Sustained release of sulfamethizole from agar beads. J Pharm Pharmacol 1979; 31: 869–872.

Fassihi AR. Characteristics of hydrogel as disintegrant in solid dose technology. J Pharm Pharmacol 1989; 54: 59–62.

Desai S, Boston S. A floating controlled-release drug delivery system: in vitro–in vivo evaluation. Pharm Res 1993; 10: 1321– 1325.

Singh KK, Deshpande SG, Baichwal MR. Studies on suppository bases: design and evaluation of sodium CMC and agar bases. Indian Drugs 1994; 31(April): 149–154.

Kahela P, Hurmerinta T, Elfving R. Effect of suspending agents on the bioavailability of erythromycin ethylsuccinate mixtures. Drug Dev Ind Pharm 1978; 4(3): 261–274.

Gennaro AR, ed. Remington: The Science and Practice of Pharmacy, 20th edn. Baltimore: Lippincott Williams & Wilkins, 2000: 1030.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 90–91.

BP: Human albumin solution PhEur: Albumini humani solutio USP: Albumin human

Synonyms

Albuconn; albumin human solution; Albuminar; Albumisol; Albuspan; Albutein; Buminate; human serum albumin; normal human serum albumin; Plasbumin; plasma albumin; Pro- Bumin; Proserum.

Chemical Name and CAS Registry Number

Serum albumin [9048-49-1]

Empirical Formula and Molecular Weight

Human serum albumin has a molecular weight of about 66 500 and is a single polypeptide chain consisting of 585 amino acids. Characteristic features are a single tryptophan residue, a relatively low content of methionine (6 residues), and a large number of cysteine (17) and of charged amino acid residues of aspartic acid (36), glutamic acid (61), lysine (59), and arginine (23).

Structural Formula

Primary structure: human albumin is a single polypeptide chain of 585 amino acids and contains seven disulfide bridges.

Secondary structure: human albumin is known to have a secondary structure that is about 55% a-helix. The remaining 45% is believed to be divided among turns, disordered, and b structures.(1)

Albumin is the only major plasma protein that does not contain carbohydrate constituents. Assays of crystalline albumin show less than one sugar residue per molecule.

Functional Category

Stabilizing agent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Albumin is primarily used as an excipient in parenteral pharmaceutical formulations, where it is used as a stabilizing agent for formulations containing proteins and enzymes.(2) Albumin has also been used to prepare microspheres and microcapsules for experimental drug-delivery systems.(3)

As a stabilizing agent, albumin has been employed in protein formulations at concentrations as low as 0.003%, although concentrations of 1–5% are commonly used. Albumin has also been used as a cosolvent(4) for parenteral drugs, as a cryoprotectant during lyophilization, and to prevent adsorp- tion of other proteins to surfaces.

Therapeutically, albumin solutions have been used parent- erally for plasma volume replacement and to treat severe acute

albumin loss. However, the benefits of using albumin in such applications in critically ill patients has been questioned.(5)

Description

The USP 28 describes albumin human as a sterile nonpyrogenic preparation of serum albumin obtained from healthy human donors; see Section 13. It is available as a solution containing 4, 5, 20, or 25 g of serum albumin in 100 mL of solution, with not less than 96% of the total protein content as albumin. The solution contains no added antimicrobial preservative but may contain sodium acetyltryptophanate with or without sodium caprylate as a stablizing agent.

The PhEur 2005 similarly describes albumin solution as an aqueous solution of protein obtained from human plasma; see Section 13. It is available as a concentrated solution containing 150–250 g/L of total protein or as an isotonic solution containing 35–50 g/L of total protein. Not less than 95% of the total protein content is albumin. A suitable stabilizer against the effects of heat, such as sodium caprylate (sodium octanoate) or N-acetyltryptophan or a combination of these two at a suitable concentration, may be added, but no antimicrobial preservative is added.

Aqueous albumin solutions are slightly viscous and range in color from almost colorless to amber depending upon the protein concentration. In the solid state, albumin appears as brownish amorphous lumps, scales, or powder.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for albumin.

Test PhEur 2005 USP 28

Identification + —

Characters + —

pH (10 g/L solution) 6.7–7.3 +

Polymers and aggregates + —

Potassium 40.05 mmol/g —

Sodium 4160 mmol/L 130–160 mEq/L

Heme + +

Aluminum 4200 mg/L —

Sterility + +

Hepatitis B surface antigen — +

Pyrogens + +

Total protein 95–105% 596%

for 4 g in 100 mL — 93.75–106.25%

for 5 to 25 g in 100 mL — 94.0–106.0%

Protein composition + —

Prekallikrein activator 435 IU/mL —

Typical Properties

Acidity/alkalinity: pH = 6.7–7.3 for a 1% w/v solution, in 0.9% w/v sodium chloride solution, at 208C.

Albumin 17

Osmolarity: a 4–5% w/v aqueous solution is isoosmotic with serum.

Solubility: freely soluble in dilute salt solutions and water. Aqueous solutions containing 40% w/v albumin can be readily prepared at pH 7.4. The high net charge of the peptide contributes to its solubility in aqueous media. The seven disulfide bridges contribute to its chemical and spatial conformation. At physiological pH, albumin has a net electrostatic charge of about –17. Aqueous albumin solu- tions are slightly viscous and range in color from almost colorless to amber depending on the protein concentration.

Stability and Storage Conditions

Albumin is a protein and is therefore susceptible to chemical degradation and denaturation by exposure to extremes of pH, high salt concentrations, heat, enzymes, organic solvents, and other chemical agents.

Albumin solutions should be protected from light and stored at a temperature of 2–258C or as indicated on the label.

Incompatibilities

med 11

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