See Section 11.

Method of Manufacture

Albumin human (USP 28) Albumin human is a sterile non- pyrogenic preparation of serum albumin that is obtained by fractionating material (source blood, plasma, serum, or pla- centas) from healthy human donors. The source material is tested for the absence of hepatitis B surface antigen. It is made by a process that yields a product safe for intravenous use.

Albumin solution, human (PhEur 2005) Human albumin solu- tion is an aqueous solution of protein obtained from plasma. Separation of the albumin is carried out under controlled con- ditions so that the final product contains not less than 95% albumin. Human albumin solution is prepared as a concen- trated solution containing 150–250 g/L of total protein or as an isotonic solution containing 35–50 g/L of total protein. 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 at any stage during preparation. The solution is passed through a bac- teria-retentive filter and distributed aseptically into sterile containers, which are then closed so as to prevent contamina- tion. The solution in its final container is heated to 60 1.08C and maintained at this temperature for not less than 10 hours. The containers are then incubated at 30–328C for not less than 14 days or at 20–258C for not less than 4 weeks and examined visually for evidence of microbial contamina- tion.

Safety

Albumin occurs naturally in the body, comprising about 60% of all the plasma proteins. As an excipient, albumin is used primarily in parenteral formulations and is generally regarded as an essentially nontoxic and nonirritant material. Adverse reactions to albumin infusion rarely occur but include nausea, vomiting, increased salivation, chills, and febrile reactions. Urticaria and skin rash have been reported. Allergic reactions,



including anaphylactic shock, can occur. Albumin infusions are contraindicated in patients with severe anemia or cardiac failure. Albumin solutions with aluminum content of less than 200 mg/L should be used in dialysis patients and premature infants.(6)

LD50 (monkey, IV): >12.5 g/kg(7) LD50 (rat, IV): >12.5 g/kg

Handling Precautions

Observe handling precautions appropriate for a biologically derived blood product.

Regulatory Acceptance

Included in the FDA Inactive Ingredients Guide (oral, tablets, film-coatings; IV injections). Included in parenteral products licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Albumins derived from animal sources are also commercially available, e.g., bovine serum albumin.

Comments

A 100 mL aqueous solution of albumin containing 25 g of serum albumin is osmotically equivalent to 500 mL of normal human plasma. The EINECS number for albumin is 310-127-6.

Specific References

Bramanti E, Benedetti E. Determination of the secondary structure of isomeric forms of human serum albumin by a particular frequency deconvolution procedure applied to Fourier transform IR analysis. Biopolymers 1996; 38(5): 639–653.

Wang JUC, Hanson MA. Parenteral formulations of proteins and peptides: stability and stabilizers. J Parenter Sci Technol 1988; 42(S): S1–S26.

Arshady R. Albumin microspheres and microcapsules: method- ology of manufacturing techniques. J Control Release 1990; 14: 111–131.

Olson WP, Faith MR. Human serum albumin as a cosolvent for parenteral drugs. J Parenter Sci Technol 1988; 42: 82–85.

Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Br Med J 1998; 317: 235–240.

Quagliaro DA, Geraci VA, Dwan RE, et al. Aluminum in albumin for injection. J Parenter Sci Technol 1988; 42: 187–190.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 1970.

General References

Kragh-Hansen U. Structure and ligand properties of human serum albumin. Danish Med Bull 1990; 37(1): 57–84.

Putnam FW, ed. The Plasma Proteins, Structure, Function and Genetic Control. London: Academic Press, 1975.

Authors

RT Guest.

Date of Revision

23 August 2005.

Alcohol

Nonproprietary Names

BP: Ethanol (96%) JP: Ethanol

PhEur: Ethanolum (96 per centum) USP: Alcohol

Synonyms

Ethyl alcohol; ethyl hydroxide; grain alcohol; methyl carbinol.

Chemical Name and CAS Registry Number

Ethanol [64-17-5]

Empirical Formula and Molecular Weight

C2H6O 46.07

Structural Formula

 

Functional Category

Antimicrobial preservative; disinfectant; skin penetrant; sol- vent.

Applications in Pharmaceutical Formulation or Technology

Ethanol and aqueous ethanol solutions of various concentra- tions (see Sections 8 and 17) are widely used in pharmaceutical formulations and cosmetics; see Table I. Although ethanol is primarily used as a solvent, it is also employed in solutions as an antimicrobial preservative.(1,2) Topical ethanol solutions are also used as penetration enhancers(3–6) and as disinfectants. Ethanol has also been used in transdermal preparations in combination with Labrasol as a co-surfactant.(7)

Table I: Uses of alcohol.

Use Concentration (% v/v)

Antimicrobial preservative 510

Disinfectant 60–90

Extracting solvent in galenical manufacture Up to 85 Solvent in film coating Variable

Solvent in injectable solutions Variable

Solvent in oral liquids Variable

Solvent in topical products 60–90

Description

In the BP 2004, the term ‘ethanol’ used without other qualification refers to ethanol containing 599.5% v/v of C2H6O. The term ‘alcohol’, without other qualification, refers

to ethanol 95.1–96.9% v/v. Where other strengths are intended, the term ‘alcohol’ or ‘ethanol’ is used, followed by the statement of the strength.

In the PhEur 2005, anhydrous ethanol contains not less than 99.5% v/v of C2H6O at 208C. The term ethanol (96%) is used to describe the material containing water and 95.1–96.9% v/v of C2H6O at 208C.

In the USP 28, the term ‘dehydrated alcohol’ refers to ethanol 599.5% v/v. The term ‘alcohol’ without other qualification refers to ethanol 94.9–96.0% v/v.

In the JP 2001, ethanol (alcohol) contains 95.1–95.6% v/v (by specific gravity) of C2H6O at 158C.

In the Handbook of Pharmaceutical Excipients, the term ‘alcohol’ is used for either ethanol 95% v/v or ethanol 96% v/v.

Alcohol is a clear, colorless, mobile, and volatile liquid with a slight, characteristic odor and burning taste.

See also Section 17.

Pharmacopeial Specifications

See Table II.

Typical Properties

Antimicrobial activity: ethanol is bactericidal in aqueous mixtures at concentrations between 60% and 95% v/v; the optimum concentration is generally considered to be 70% v/v. Antimicrobial activity is enhanced in the presence of edetic acid or edetate salts.(1) Ethanol is inactivated in the presence of nonionic surfactants and is ineffective against bacterial spores.

Boiling point: 78.158C

Flammability: readily flammable, burning with a blue, smoke- less flame.

Flash point: 148C (closed cup)

Solubility: miscible with chloroform, ether, glycerin, and water (with rise of temperature and contraction of volume).

Specific gravity: 0.8119–0.8139 at 208C

Note: the above typical properties are for alcohol (ethanol 95% or 96% v/v). See Section 17 for typical properties of dehydrated alcohol.

Stability and Storage Conditions

Aqueous ethanol solutions may be sterilized by autoclaving or by filtration and should be stored in airtight containers, in a cool place.

Incompatibilities

In acidic conditions, ethanol solutions may react vigorously with oxidizing materials. Mixtures with alkali may darken in color owing to a reaction with residual amounts of aldehyde. Organic salts or acacia may be precipitated from aqueous solutions or dispersions. Ethanol solutions are also incompa- tible with aluminum containers and may interact with some drugs.

Alcohol 19 

Table II: Pharmacopeial specifications for alcohol.

Fusel oil constituents + — —



containing beverages, many pharmaceutical products contain ethanol as a solvent, which, if ingested in sufficiently large quantities, may cause adverse symptoms of intoxication. In the USA, the maximum quantity of alcohol included in OTC medicines is 10% v/v for products labeled for use by people of 12 years of age and older, 5% v/v for products intended for use by children aged 6–12 years of age, and 0.5% v/v for products for use by children under 6 years of age.(8)

Parenteral products containing up to 50% of alcohol (ethanol 95 or 96% v/v) have been formulated. However, such concentrations can produce pain on intramuscular injection and lower concentrations such as 5–10% v/v are preferred. Subcutaneous injection of alcohol (ethanol 95% v/v) similarly causes considerable pain followed by anesthesia. If injections are made close to nerves, neuritis and nerve degeneration may occur. This effect is used therapeutically to cause anesthesia in cases of severe pain, although the practice of using alcohol in nerve blocks is controversial. Doses of 1 mL of absolute alcohol have been used for this purpose.(9)

Preparations containing more than 50% v/v alcohol may

Acetone and

propan-2-ol

— — +

cause skin irritation when applied topically.

Methanol — 4 200 ppm +

Benzene — 4 2 ppm —

LD50 (mouse, IP): 0.93 g/kg(10) LD50 (mouse, IV): 1.97 g/kg

Acetaldehyde and acetal

Reducing

substances Organic volatile

impurities

— 4 10 ppm —

+ — —

— — +

LD50 (mouse, oral): 3.45 g/kg LD50 (mouse, SC): 8.29 g/kg LD50 (rat, IP): 3.75 g/kg

LD50 (rat, IV): 1.44 g/kg LD50 (rat, oral): 7.06 g/kg

Chloride + — —

Heavy metals 41.2 ppm — —

Assay 95.1–95.6% 95.1–96.9% 92.3–93.8%

by weight 94.9–96.0%

by volume

Method of Manufacture

Ethanol is manufactured by the controlled enzymatic fermenta- tion of starch, sugar, or other carbohydrates. A fermented liquid is produced containing about 15% ethanol; ethanol 95% v/v is then obtained by fractional distillation. Ethanol may also be prepared by a number of synthetic methods.

Safety

Ethanol and aqueous ethanol solutions are widely used in a variety of pharmaceutical formulations and cosmetics. It is also consumed in alcoholic beverages.

Ethanol is rapidly absorbed from the gastrointestinal tract and the vapor may be absorbed through the lungs; it is metabolized, mainly in the liver, to acetaldehyde, which is further oxidized to acetate.

Ethanol is a central nervous system depressant and ingestion of low to moderate quantities can lead to symptoms of intoxication including muscle incoordination, visual impair- ment, slurred speech, etc. Ingestion of higher concentrations may cause depression of medullary action, lethargy, amnesia, hypothermia, hypoglycemia, stupor, coma, respiratory depres- sion, and cardiovascular collapse. The lethal human blood- alcohol concentration is generally estimated to be 400–500 mg/ 100 mL.

Although symptoms of ethanol intoxication are usually encountered following deliberate consumption of ethanol-

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Ethanol and aqueous ethanol solutions should be handled in a well-ventilated environment. In the UK, the long-term 8-hour TWA exposure limit for ethanol is 1920 mg/m3 (1000 ppm).(11) Ethanol may be irritant to the eyes and mucous membranes and eye protection and gloves are recommended. Ethanol is flammable and should be heated with care. Fixed storage tanks should be electrically grounded to avoid ignition from electrostatic discharges when ethanol is transferred.

Regulatory Status

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

Related Substances

Dehydrated alcohol; denatured alcohol; dilute alcohol; iso- propyl alcohol.

Dehydrated alcohol

Synonyms: absolute alcohol; anhydrous ethanol; ethanol.

Autoignition temperature: 3658C

Boiling point: 78.58C

Explosive limits: 3.5–19.0% v/v in air Flash point: 128C (closed cup) Melting point: —1128C

Moisture content: absorbs water rapidly from the air.

20 Alcohol

Refractive index: n20 = 1.361

Specific gravity: 0.7904–0.7935 at 208C

Surface tension: 22.75 mN/m at 208C (ethanol/vapor)

Vapor density (relative): 1.59 (air = 1)

Vapor pressure: 5.8 Pa at 208C

Viscosity (dynamic): 1.22 mPa s (1.22 cP) at 208C

Comments: dehydrated alcohol is ethanol 599.5% v/v. See

Section 8.

Denatured alcohol

Synonyms: industrial methylated spirit; surgical spirit.

Comments: denatured alcohol is alcohol intended for external use only. It has been rendered unfit for human consumption by the addition of a denaturing agent such as methanol or methyl isobutyl ketone.

Dilute alcohol

Synonyms: dilute ethanol.

Specific gravity: see Table III.

Table III: Specific gravity of alcohol.

Strength of alcohol (% v/v) Specific gravity at 208C

90 0.8289–0.8319

80 0.8599–0.8621

70 0.8860–0.8883

60 0.9103–0.9114

50 0.9314–0.9326

45 0.9407–0.9417

25 0.9694–0.9703

20 0.9748–0.9759

Comments: the term ‘dilute alcohol’ refers to a mixture of ethanol and water of stated concentration. The BP 2004 lists eight strengths of dilute alcohol (dilute ethanol) containing 90%, 80%, 70%, 60%, 50%, 45%, 25%, and 20% v/v

respectively of ethanol.

Comments

Possession and use of nondenatured alcohols are usually subject to close control by excise authorities.

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

The EINECS number for alcohol is 200-578-6.

Specific References

Chiori CO, Ghobashy AA. A potentiating effect of EDTA on the bactericidal activity of lower concentrations of ethanol. Int J Pharm 1983; 17: 121–128.

Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation of preservative efficacy. IV. The determination of antimicrobial characteristics of some pharmaceutical compounds in aqueous solutions. Int J Pharm 1989; 54: 51–56.

Liu P, Higuchi WI, Song W, et al. Quantitative evaluation of ethanol effects on diffusion and metabolism of b-estradiol in hairless mouse skin. Pharm Res 1991; 8(7): 865–872.

Verma DD, Fahr A. Synergistic penetration enhancement of ethanol and phospholipids on the topical delivery of cyclosporin

A. J Controlled Release 2004; 97(1): 55–66.

Gwak SS, Oh IS, Chun IK. Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers. Drug Dev Ind Pharm 2004; 30(2): 187–194.

Williams AC, Barry BW. Penetration enhancers. Adv Drug Delivery Rev 2004; 56(5): 603–618.

Kwean JH, Chi SC, Park ES. Transdermal delivery of diclofenac using microemulsions. Arch Pharmacol Res 2004; 27(3): 351–356.

Jass HE. Regulatory review. Cosmet Toilet 1995; 110(5): 21–22.

Lloyd JW. Use of anaesthesia: the anaesthetist and the pain clinic.

Br Med J 1980; 281: 432–434.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 1627–1628.

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

General References

Lund W, ed. The Pharmaceutical Codex: Principles and Practice of Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994: 694–695.

Spiegel AJ, Noseworthy MN. Use of nonaqueous solvents in parenteral products. J Pharm Sci 1963; 52: 917–927.

Wade A, ed. Pharmaceutical Handbook, 19th edn. London: Pharma- ceutical Press, 1980: 227–230.

Authors

SC Owen.

Date of Revision

10 February 2005.

Alginic Acid

Nonproprietary Names

BP: Alginic acid

PhEur: Acidum alginicum USPNF: Alginic acid

Synonyms

E400; Kelacid; L-gulo-D-mannoglycuronan; polymannuronic acid; Protacid; Satialgine H8.

Chemical Name and CAS Registry Number

Alginic acid [9005-32-7]

Empirical Formula and Molecular Weight

Alginic acid is a linear glycuronan polymer consisting of a mixture of b-(1→4)-D-mannosyluronic acid and a-(1→4)-L- gulosyluronic acid residues, of general formula (C6H8O)n. The molecular weight is typically 20 000–240 000.

Structural Formula

The PhEur 2005 describes alginic acid as a mixture of polyuronic acids [(C6H8O6)n] composed of residues of D-mannuronic and L-glucuronic acid, and is obtained mainly from algae belonging to the Phaeophyceae. A small proportion of the carboxyl groups may be neutralized.

See also Section 4.

Functional Category

Stabilizing agent; suspending agent; sustained release adjuvant; tablet binder; tablet disintegrant; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Alginic acid is used in a variety of oral and topical pharmaceutical formulations. In tablet and capsule formula- tions, alginic acid is used as both a binder and disintegrating agent at concentrations of 1–5% w/w.(1,2) Alginic acid is widely used as a thickening and suspending agent in a variety of pastes, creams, and gels; and as a stabilizing agent for oil-in-water emulsions. Alginic acid has also been investigated for use in an ocular formulation of carteolol.(3)

Therapeutically, alginic acid has been used as an antacid.(4) In combination with an H2-receptor antagonist, it has also been utilized for the management of gastroesophageal reflux.(5) Chemically modified alginic acid derivatives have been researched for their anti-inflammatory, antiviral, and anti- tumoral activities.(6)

In the area of controlled release, the preparation of indomethacin sustained-release microparticles from alginic acid (alginate)–gelatin hydrocolloid coacervate systems has been investigated.(7) In addition, as controlled-release systems for liposome-associated macromolecules, microspheres have been produced encapsulating liposomes coated with alginic

acid and poly-L-lysine membranes.(8) Alginate gel beads capable of floating in the gastric cavity have been prepared, the release properties of which were reported to be applicable for sustained release of drugs, and for tareting the gastric mucosa.(9) Alginic acid has also been used to improve the stability of levosimendan.(10) Mechanical properties, water uptake, and permeability properties of a sodium salt of alginic acid have been characterized for controlled-release applica- tions.(11) In addition, sodium alginate has been incorporated into an ophthalmic drug delivery system for pilocarpine nitrate.(12) It has also been reported that associated chains of alginic acid complexed with cations can bind to cell surfaces and exert pharmacological effects which depend on the cell type and the complexed cation. These complexes can be used to treat rheumatic disorders, diseases associated with atopic diathesis and liver diseases.(13) Furthermore, an alginic oligosaccharide, obtained from a natural edible polysaccharide, has been shown to suppress Th2 responses and IgE production by inducing IL-12 production, was found to be a useful approach for preventing allergic disorders.(14)

SEM: 1

Excipient: Alginic acid

Magnification: 100×

Voltage: 25 kV

 

Description

Alginic acid is a tasteless, practically odorless, white to yellowish-white, fibrous powder.

Pharmacopeial Specifications

See Table I.

22 Alginic Acid

SEM: 2

Excipient: Alginic acid

Magnification: 500×

Voltage: 25 kV

 

Table I: Pharmacopeial specifications for alginic acid

Test PhEur 2005 USPNF 23

Identification + +

Characters + —

Microbial limits 4102/g 4200/g

pH (3% dispersion) — 1.5–3.5

Loss on drying 415.0% 415.0%

Ash — 44.0%

Sulfated ash 48.0% —

Arsenic — 43 ppm

Chloride 41.0% —

Lead — 40.001%

Heavy metals 420 ppm 40.004% Acid value (dried basis) — 5230 Assay (of COOH groups) 19.0–25.0% —

Typical Properties

Acidity/alkalinity: pH = 1.5–3.5 for a 3% w/v aqueous dispersion.

Crosslinking: addition of a calcium salt, such as calcium citrate or calcium chloride, causes crosslinking of the alginic acid polymer resulting in an apparent increase in molecular weight. Films crosslinked with triphosphate (tripolypho- sphate) and calcium chloride were found to be insoluble but permeable to water vapor. Drug permeability varies with pH and the extent of crosslinking.(11)

Density (true): 1.601 g/cm3

Moisture content: 7.01%

Solubility: soluble in alkali hydroxides, producing viscous solutions; very slightly soluble or practically insoluble in ethanol (95%) and other organic solvents. Alginic acid

swells in water but does not dissolve; it is capable of absorbing 200–300 times its own weight of water.

Viscosity (dynamic): various grades of alginic acid are commercially available that vary in their molecular weight and hence viscosity. Viscosity increases considerably with increasing concentration; typically a 0.5% w/w aqueous dispersion will have a viscosity of approximately 20 mPa s, while a 2.0% w/w aqueous dispersion will have a viscosity of approximately 2000 mPa s. The viscosity of dispersions decreases with increasing temperature. As a general rule, a 18C increase in temperature results in a 2.5% reduction in viscosity. At low concentrations, the viscosity of an alginic acid dispersion may be increased by the addition of a calcium salt, such as calcium citrate. See also Sections 11 and 18.

Stability and Storage Conditions

Alginic acid hydrolyzes slowly at warm temperatures produ- cing a material with a lower molecular weight and lower dispersion viscosity.

Alginic acid dispersions are susceptible to microbial spoilage on storage, which may result in some depolymerization and hence a decrease in viscosity. Dispersions should therefore be preserved with an antimicrobial preservative such as benzoic acid; potassium sorbate; sodium benzoate; sorbic acid; or paraben. Concentrations of 0.1–0.2% are usually used.

Alginic acid dispersions may be sterilized by autoclaving or filtration through a 0.22 mm filter. Autoclaving may result in a decrease in viscosity which can vary depending upon the nature of any other substances present.(15)

Alginic acid should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Incompatible with strong oxidizing agents, alginic acid forms insoluble salts in the presence of alkaline earth metals and group III metals with the exception of magnesium.

Method of Manufacture

Alginic acid is a hydrophilic colloid carbohydrate that occurs naturally in the cell walls and intercellular spaces of various species of brown seaweed (Phaeophyceae). The seaweed occurs widely throughout the world and is harvested, crushed, and treated with dilute alkali to extract the alginic acid.

Safety

Alginic acid is widely used in food products and topical and oral pharmaceutical formulations. It is generally regarded as a nontoxic and nonirritant material, although excessive oral consumption may be harmful. Inhalation of alginate dust may be irritant and has been associated with industrially related asthma in workers involved in alginate production. However, it appears that the cases of asthma were linked to exposure to unprocessed seaweed dust rather than pure alginate dust.(16) An acceptable daily intake of alginic acid and its ammonium, calcium, potassium, and sodium salts was not set by the WHO because the quantities used, and the background levels in food, did not represent a hazard to health.(17)

LD50 (rat, IP): 1.6 g/kg(18)

Alginic Acid 23 

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Alginic acid may be irritant to the eyes or respiratory system if inhaled as dust; see Section

14. Eye protection, gloves, and a dust respirator are recom- mended. Alginic acid should be handled in a well-ventilated environment.

Regulatory Status

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

Related Substances

Ammonium alginate; calcium alginate; potassium alginate; propylene glycol alginate; sodium alginate.