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Stability and Storage Conditions

Water is chemically stable in all physical states (ice, liquid, and vapor). Water for specific purposes should be stored in appropriate containers; see Table III.

Table II: Pharmacopeial specifications of water for different pharmaceutical applications.

Test Water

JP 2001 Purified water

JP 2001 Purified

water in bulk Purified water in

containers Purified Water,

water highly USP 28 purified Sterile

water for injection Bacteriostatic water for

injection Sterile

water for inhalation Sterile

water for irrigation Sterile Water for

purified injection(a) water JP 2001 Water for

injection Water for injection

(in bulk) Sterile

water for injection Sterile

purified water

PhEur 2005 PhEur 2005 PhEur 2005 USP 28 USP 28 USP 28 USP 28 USP 28 USP 28 PhEur PhEur 2005 JP 2001

Suppl. 1 Suppl. 1 Suppl. 1 2005

Identification — — — — — — — — — —

Production — — + — — + — — — — Characters + + + + — + — — — —

Appearance of solution

Cadmium 40.01 mg/L — — — — — — — — — — — — — — —

Chloride 4200 mg/L + — + — — + — + + + + + — + +

Cyanide 40.01 mg/L — — — — — — — — — — — — — — —

Copper 41 mg/L — — — — — — — — — — — — — — — Sulfate — + — + — — + + + + + + + — + +

Ammonium 40.05 mg/L 40.05 mg/L — 40.2 ppm — — + — + + + + + — 40.2 ppm 40.05 mg/L Iron 40.3 ppm — — — — — — — — — — — — — — —

Calcium — — — + — — + + + + + — + — + —

Lead 40.1 mg/L — — — — — — — — — — — — — — —

Magnesium — — — + — — — — — — — — — — + —

Aluminum — — 410 ppb — — 410 ppb — — — — — — — 410 ppb — — Nitrate — — 40.2 ppm — — 40.2 ppm — — — — — + — 40.2 ppm 40.2 ppm +

Nitrogen from nitrate

Nitrogen from nitrite

�410 mg/L + — — — — — — — — — — — — — —

+ + — — — — — — — — — — — — — —

Carbon dioxide — — — — — — + + + + + — + — — — Heavy metals 41 mg/L + 40.1 ppm + — 40.1 ppm — — — — — + — 40.1 ppm + +

Oxidizable

substances Potassium

permanganate- reducing substances

Residue on

evaporation Total organic

carbon

�— — — + — — + — + + + — + — + —

410 mg/L + — — — — — — — — — — — — — —

4500 mg/L 41.0 mg — 40.001% — — — — — — — + — — + 41.0 mg

— — — — + 40.5 mg/L — — — — — +(b) + 40.5 mg/L + —

Anionic surfactants Antimicrobial

agents Sterility Particulate matter Microbial

contamination Bacterial

endotoxins

�for containers 410 ml, 45 mS/cm for containers 510 ml

(a) For water for injection preserved in containers and sterilized, the JP 2001 provides separate tests for acid or alkali, chloride, ammonium, and residue on evaporation within the monograph.

(b) For water for injection prepared by reverse osmosis–ultrafiltration.

804 Water

Table III: Storage requirements for different grades of water.

Type Storage requirements(a)

�processes, such as distillation; deionization; or reverse osmo- sis.(1,3–8)

Bacteriostatic water for injection

�Preserve in single-dose and multiple-dose containers, preferably of Type I or Type II glass, not larger than 30 mL in size.

�Distillation A wide variety of stills are available to produce purified or distilled water. A typical design consists of an eva- porator, vapor separator, and compressor. The distilland (raw

Potable water Preserve in tightly sealed containers.

Purified water Preserve in tightly sealed containers. If it is

stored in bulk, the conditions of storage should be designed to limit the growth of microorganisms and avoid any other

contamination.

�feed water) is heated in the evaporator to boiling and the

vapor produced is separated from entrained distilland in the separator. The vapor then enters a compressor where the tem- perature of the vapors is raised to 1078C. Superheated vapors are then condensed on the outer surface of the tubes of the evaporator containing cool distilland circulating within.

Sterile water for inhalation Sterile water for injection

�Preserve in single-dose containers, preferably of Type I or Type II glass.

Preserve in single-dose containers, preferably of Type I or Type II glass, not more than

1000 mL in size.

�Vapor compression stills of various sizes are commercially available and can be used to produce water of high purity when properly constructed. A high-quality distillate, such as water for injection, can be obtained if the water is first deionized. The best stills are constructed of types 304 or 316 stainless steel and

Water for injection Preserve in tightly sealed containers.

�coated with pure tin, or are made from chemical-resistant glass.

Water for injections in bulk

�Collect and store in conditions designed to prevent growth of microorganisms and avoid any other contamination.

�De-ionization Cationic and anionic ion exchange resins are used to purify potable water by removing any dissolved ions. Dissolved gases are also removed, while chlorine, in the con-

(a) To prevent evaporation and to maintain quality.

Incompatibilities

In pharmaceutical formulations, water can react with drugs and other excipients that are susceptible to hydrolysis (decomposi- tion in the presence of water or moisture) at ambient and elevated temperatures.

Water can react violently with alkali metals and rapidly with alkaline metals and their oxides, such as calcium oxide and magnesium oxide. Water also reacts with anhydrous salts to form hydrates of various compositions, and with certain organic materials and calcium carbide.

Method of Manufacture

Unlike other excipients, water is not purchased from outside suppliers but is manufactured in-house by pharmaceutical companies. The selection of the most appropriate system and the overall design of the system are crucial factors to ensure that water of the correct quality is produced.(1,2)

To produce potable or drinking water, insoluble matter is first removed from a water supply by coagulation, settling, and filtering processes. Pathogenic microorganisms present are then destroyed by aeration, chlorination, or some other means. Water may also be rendered free of viable pathogenic microorganisms by active boiling for 15–20 minutes. Finally, the palatability of the water is improved by aeration and charcoal filtration.

The quality attributes of water for injection (WFI) are stricter than for purified water. Consequently, the preparation methods typically vary in the last stage to ensure good control of quality of WFI. Methods for the production of WFI are the subject of current debate. The PhEur 2005 indicates that only distillation would give assurance of consistent supply of the appropriate quality. However, the PhEur 2005 permits distilla- tion, ion exchange, reverse osmosis, or any other suitable method that complies with regulations on water intended for human consumption laid down by the competent authority.

The USP 28 and the JP 2001 permit the use of reverse osmosis (RO) in addition to distillation and ultrafiltration. Purified water suitable for use in pharmaceutical formulations is usually prepared by purifying potable water by one of several

�centrations generally found in potable water, is destroyed by the resin itself. Some organics and colloidal particles are removed by adsorption and filtration. Resin beds may, how- ever, foster microbial life and produce pyrogenic effluent unless adequate precautions are taken to prevent contamina- tion. Mixed-bed units produce purer water (lower conductiv- ity) than do stills. However, the organic matter content is usually higher. Ion exchange units are normally used today to treat raw feed water prior to distillation or reverse osmosis processing.

Reverse osmosis Water is forced through a semipermeable membrane in the opposite direction to normal osmotic diffu- sion. A very small proportion of inorganic salts passes through, but undissolved materials (bacteria and large mole- cules such as viruses, pyrogens, and high-molecular-weight organics) are removed.

Ultrafiltration A permeable membrane is used for mechanical separation. Impurities including endotoxins are removed by the membrane.

Safety

Water is the base for many biological life forms, and its safety in pharmaceutical formulations is unquestioned provided it meets standards of quality for potability(9) and microbial content; see Sections 9 and 18. Plain water is considered slightly more toxic upon injection into laboratory animals than physiological salt solutions such as normal saline or Ringer’s solution.

Ingestion of excessive quantities of water can lead to water intoxication, with disturbances of the electrolyte balance.

Water for injection should be free from pyrogens.

LD50 (mouse, IP): 25 g/kg(10)

Handling Precautions

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

Water 805

Regulatory Status

Included in nonparenteral and parenteral medicines licensed in the UK and USA.

Related Substances

Bacteriostatic water for injection; carbon dioxide-free water; de-aerated water; hard water; soft water; sterile water for inhalation; sterile water for injection; sterile water for irriga- tion; water for injection.

Bacteriostatic water for injection

Comments: the USP 28 (Suppl. 1.0) describes bacteriostatic water for injection as sterile water for injection that contains one or more suitable antimicrobial agents.

Carbon dioxide-free water

Comments: purified water that has been boiled vigorously for 5 minutes and allowed to cool while protecting it from absorption of atmospheric carbon dioxide.

De-aerated water

Comments: purified water that has been boiled vigorously for 5 minutes and cooled to reduce the air (oxygen) content.

Hard water

Comments: water containing the equivalent of not less than 120 mg/L and not more than 180 mg/L of calcium carbo- nate.

Soft water

�

Without further purification, ‘water’ may be unsuitable for certain pharmaceutical applications; for example, the presence of calcium in water affects the viscosity and gel strength of algins and pectin dispersions, while the use of potable water affects the clarity and quality of cough mixtures, and the stability of antibiotic liquid preparations.

Water commonly contains salts of aluminum, calcium, iron, magnesium, potassium, sodium, and zinc. Toxic substances such as arsenic, barium, cadmium, chromium, cyanide, lead, mercury, and selenium may constitute a danger to health if present in excessive amounts. Ingestion of water containing high amounts of calcium and nitrate is also contraindicated. National standards generally specify the maximum limits for these inorganic substances in potable water. Limits have also been placed on microorganisms, detergents, phenolics, chlori- nated phenolics, and other organic substances. The WHO(11) and national bodies have issued guidelines for water quality, although many countries have their own standards for water quality embodied in specific legislation.(12) See Table IV.

Control of microbiological contamination is critical for waters used in preparation of pharmaceuticals as proliferation of microorganisms can potentially occur during all stages of manufacture, storage, or distribution. Suitable control is achieved by ensuring that the water system is well designed and well maintained. Purified water that is produced, stored, and circulated at ambient temperatures is susceptible to the establishment of biofilms; therefore, frequent monitoring, high usage, correct flow rate, and appropriate sanitization are all factors that require consideration to ensure that water is satisfactory.(13)

Table IV: Limits for inorganic substances in potable water (mg/L).

Comments: water containing the equivalent of not more than

60 mg/L of calcium carbonate.

Sterile water for inhalation

Comments: the USP 28 (Suppl. 1.0) describes sterile water for inhalation as water purified by distillation or by reverse osmosis and rendered sterile. It contains no antimicrobial agents or other added substances, except where used in humidifiers or other similar devices, and where liable to contamination over a period of time.

Sterile water for injection

Comments: the USP 28 describes sterile water for injection as water for injection sterilized and suitably packaged. It contains no antimicrobial agents or other substances.

Sterile water for irrigation

Comments: the USP 28 describes sterile water for irrigation as water for injection sterilized and suitably packaged. It contains no antimicrobial agents or other substances.

Water for injection

Comments: the USP 28 describes water for injection as water purified by distillation or reverse osmosis. It contains no added substances. The PhEur 2005 title is ‘water for injections’ and comprises two parts: ‘water for injections in bulk’ and ‘sterilized water for injection.’ The PhEur 2005 states that water for injections is produced by distillation.

Comments

In most pharmacopeias, the term ‘water’ now refers to purified or distilled water.

�Contaminant UK (mg/L) WHO (mg/L)

Nitrate (as NO3) 50 —

Nitrite (as NO2) 0.1 —

Monitoring of the whole system is essential in order to demonstrate that correct microbiological quality is achieved. For WFI the recommended methodology is membrane filtration (0.45 mm) as a large sample size (100–300 mL) is required. For purified water, membrane filtration or plate count methods are typically used depending on the quality requirements of the system. It is important to set appropriate target, alert, and action limits to serve as an indication of action required to bring the quality of water back under control. It is recognized that limits are not intended as pass/fail criteria for water or product batches; however, an investigation regarding the implications should be conducted.(14)

Validation is conducted to provide a high level of assurance that the water production and distribution system will consistently produce water conforming to a defined quality specification. The validation process serves to qualify the design (DQ), installation (IQ), operation (OQ), and performance (PQ) of the system. The extent of monitoring data required should be defined, with consideration given to whether validation to FDA guidelines is required.(14) It is also important to have an ongoing control program with respect to maintenance and periodic reviews of the performance of the water system.

Specific References

Thomas WH, Harvey H. Achieving purity in pharmaceutical water. Manuf Chem Aerosol News 1976; 47(10): 32, 36, 39, 40.

McWilliam AJ. High purity water distribution systems. Pharm Eng 1995; Sept/Oct: 54–71.

Honeyman T. Purified water for pharmaceuticals. Manuf Chem

1987; 58(3): 53, 54, 57, 59.

Cross J. Treating waters for the pharmaceutical industry. Manuf Chem 1988; 59(3): 34–35.

Cross J. Steam sterilisable ultrafiltration membranes. Manuf Chem 1989; 60(3): 25–27.

�Horry JM, Cross JR. Purifying water for ophthalmic and injectable preparations. Pharm J 1989; 242: 169–171.

Smith VC. Pure water. Manuf Chem 1990; 61(3): 22–24.

Burrows WD, Nelson JH. IV fluidmakers: preparation of sterile water for injection in a field setting. J Parenter Sci Technol 1993; 47(3): 124–129.

Walker A. Drinking water – doubts about quality. Br Med J 1992;

304: 175–178.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3692.

World Health Organization. Guidelines for Drinking-water Quality, vol. 1: Recommendations. Geneva: WHO, 1984.

Statutory Instrument 1147. The water supply (water quality) regulations 1989. London: HMSO, 1989.

Riedewald F. Biofilms in pharmaceutical waters. Pharm Eng 1997;

Nov/Dec: 8–18.

Food and Drug Administration. Guide to Inspections of High Purity Water Systems. Washington, DC: FDA, 1993.

General References

Santoro M, Maini C. Which water for pharmaceutical use? Eur J Parenter Pharm Sci 2003; 8: 15–20.

Ro¨ ssler R. Water and air, two important media in the manufacture of sterile pharmaceuticals, with regard to the GMP. Drugs Made Ger 1976; 19: 130–136.

Wax, Anionic Emulsifying

Nonproprietary Names

BP: Emulsifying wax

Synonyms

Collone HV; Crodex A; Cyclonette Wax; Lanette wax SX BP.

Chemical Name and CAS Registry Number

Anionic emulsifying wax [8014-38-8]

Empirical Formula and Molecular Weight

The BP 2004 describes anionic emulsifying wax as containing cetostearyl alcohol, purified water, and either sodium lauryl sulfate or a sodium salt of a similar sulfated higher primary aliphatic alcohol. See also Sections 13 and 18.

Structural Formula

See Section 4.

Functional Categories

Emulsifying agent; stiffening agent.

Applications in Pharmaceutical Formulation or Technology

Anionic emulsifying wax is used in cosmetics and topical pharmaceutical formulations primarily as an emulsifying agent. The wax is added to fatty or paraffin bases to facilitate the production of oil-in-water emulsions that are nongreasy. In concentrations of about 2%, emulsions are pourable; stiffer emulsions, e.g., aqueous cream BP, may contain up to 10% of anionic emulsifying wax.

Creams should be adequately preserved and can usually be sterilized by autoclaving. A better-quality emulsion is produced by incorporating some alkali into the aqueous phase, although care should be taken not to use an excess.

Anionic emulsifying wax (3–30%) may also be mixed with soft and liquid paraffins to prepare anhydrous ointment bases such as emulsifying ointment BP. A preparation of 80% anionic emulsifying wax in white soft paraffin has been used as a soap substitute in the treatment of eczema.

In addition, anionic emulsifying wax (10%) has been added to theobroma oil to produce a suppository base with a melting point of 348C.

Description

An almost white or pale yellow colored, waxy solid or flakes which when warmed become plastic before melting. Anionic emulsifying wax has a faint characteristic odor and a bland taste.

�Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for anionic emulsifying wax.

Saponification value 42.0

Sodium alkyl sulfates 58.7%

Sulfated ash 2.5–4.0%

Unsaponifiable matter 586.0%

Water 44.0%

Typical Properties

Density: 0.97 g/cm3 Flash point: >1008C Melting point: 528C

Solubility: soluble in chloroform, ethanol (95%), ether, and, on warming, in fixed oils and mineral oil; practically insoluble in water, forming an emulsion.

Stability and Storage Conditions

Solid anionic emulsifying wax is chemically stable and should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Incompatibilities of anionic emulsifying wax are essentially those of sodium alkyl sulfates and include cationic compounds (quaternary ammonium compounds, acriflavine, ephedrine hydrochloride, antihistamines, and other nitrogenous com- pounds), salts of polyvalent metals (aluminum, zinc, tin, and lead), and thioglycollates. Anionic emulsifying wax is compa- tible with most acids above pH 2.5. It is also compatible with alkalis and hard water.

Iron vessels should not be used when heating anionic emulsifying wax; stainless steel containers are satisfactory.

Method of Manufacture

Anionic emulsifying wax is prepared by melting cetostearyl alcohol and heating to about 958C. Sodium lauryl sulfate, or some other suitable anionic surfactant, and purified water are then added. The mixture is heated to 1158C and, while this temperature is maintained, the mixture is stirred vigorously until any frothing ceases. The wax is then rapidly cooled.

The BP 2004 specifies that the formula of anionic emulsifying wax is:

Cetostearyl alcohol 90 g Sodium lauryl sulfate 10 g Purified water 4 mL

808 Wax, Anionic Emulsifying

Safety

Anionic emulsifying wax is used primarily in topical pharma- ceutical formulations and is generally regarded as a nontoxic and nonirritant material. However, sodium lauryl sulfate, a constituent of anionic emulsifying wax, is known to be irritant to the skin at high concentrations; sodium cetyl sulfate is claimed to be less irritating.

Emulsifying ointment BP, which contains anionic emulsify- ing wax, has been found to have major sunscreen activity in clinically normal skin and should therefore not be used before phototherapy procedures.(1)

Handling Precautions

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

Regulatory Status

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

Related Substances

Cetostearyl alcohol; sodium lauryl sulfate; wax, nonionic emulsifying.

A number of emulsifying waxes are commercially available that contain different sodium alkyl sulfates and may not meet official compendial specifications. See also Section 18.

Comments

The nomenclature for emulsifying wax is confused since there are three groups of emulsifying waxes, with different titles in the UK and USA; see Table II.

�Table II: Nomenclature for emulsifying wax.

UK USA

Nonionic Cetomacrogol emulsifying wax Emulsifying wax Anionic Emulsifying wax —

Cationic Cetrimide emulsifying wax —

The waxes have similar physical properties but vary in the type of surfactant used, which, in turn, affects the range of compatibilities. Emulsifying wax BP and emulsifying wax USP contain anionic and nonionic surfactants, respectively, and are therefore not interchangeable in formulations.

Specific References

1 Cox NH, Sharpe G. Emollients, salicylic acid, and ultraviolet erythema [letter]. Lancet 1990; 335: 53–54.

General References

Eccleston GM. Properties of fatty alcohol mixed emulsifiers and emulsifying waxes. In: Florence AT, ed. Materials Used in Pharmaceutical Formulation: Critical Reports on Applied Chem- istry, vol. 6. Oxford: Blackwell Scientific, 1984: 124–156.

BP: Carnauba wax JP: Carnauba wax PhEur: Cera carnauba

USPNF: Carnauba wax

Synonyms

Brazil wax; caranda wax; E903.

Chemical Name and CAS Registry Number

Carnauba wax [8015-86-9]

Empirical Formula and Molecular Weight

Carnauba wax consists primarily of a complex mixture of esters of acids and hydroxy acids, mainly aliphatic esters, o- hydroxy esters, p-methoxycinnamic aliphatic esters, and p- hydroxycinnamic aliphatic diesters composed of several chain lengths, in which C26 and C32 alcohols are the most prevalent.(1)

Also present are acids, oxypolyhydric alcohols, hydrocar- bons, resinous matter, and water.

Applications in Pharmaceutical Formulation or Technology

Carnauba wax is widely used in cosmetics, certain foods, and pharmaceutical formulations. Cosmetically, carnauba wax is commonly used in lip balms.(2)

Carnauba wax is the hardest and highest-melting of the waxes commonly used in pharmaceutical formulations and is used primarily as a 10% w/v aqueous emulsion to polish sugar- coated tablets. Aqueous emulsions may be prepared by mixing carnauba wax with an ethanolamine compound and oleic acid. The carnauba wax coating produces tablets of good luster without rubbing. Carnauba wax may also be used in powder form to polish sugar-coated tablets.

Carnauba wax (10–50% w/w) is also used alone or with other excipients such as hypromellose, hydroxypropyl cellu- lose, alginate/pectin-gelatin, Eudragit, and stearyl alcohol to produce sustained-release solid-dosage formulations.(3–10)

Additionally, carnauba wax has been experimentally investigated for use in producing microparticles in a novel hot air coating (HAC) process developed as an alternative to conventional spray-congealing techniques.(11)

�Description

Carnauba wax occurs as a light brown- to pale yellow-colored powder, flakes, or irregular lumps of a hard, brittle wax. It has a characteristic bland odor and practically no taste. It is free from rancidity. Various types and grades are available commercially.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for carnauba wax.

Test JP 2001 PhEur 2005 USPNF 23

Characters + + —

Identification — + —

Appearance of solution — + —

Melting range 80–868C 80–888C 80–868C

Acid value 410.0 2–7 2–7

Saponification value 78–95 78–95 78–95

Total ash — 40.25% 40.25%

Heavy metals — — 420 mg/g

Organic volatile impurities — — +

Iodine value 5–14 — —

Specific gravity 0.990–1.002 — —

Typical Properties

Flash point: 270–3308C

Refractive index: n90 = 1.450

Solubility: soluble in warm chloroform and in warm toluene; slightly soluble in boiling ethanol (95%); practically insoluble in water.

Specific gravity: 0.990–0.999 at 258C

Unsaponified matter: 50–55%

Stability and Storage Conditions

Carnauba wax is stable and should be stored in a well-closed container, in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Carnauba wax is obtained from the leaf buds and leaves of the Brazilian carnauba palm, Copernicia cerifera. The leaves are dried and shredded and the wax is then removed by the addition of hot water.

Safety

Carnauba wax is widely used in oral pharmaceutical formula- tions, cosmetics, and certain food products. It is generally regarded as an essentially nontoxic and nonirritant ma- terial.(12–14)

810 Wax, Carnauba

There have been reports of allergic contact dermatitis from carnauba wax in mascara.(15)

The WHO has established an acceptable daily intake of up to 7 mg/kg body-weight for carnauba wax.(16)

Handling Precautions

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

Regulatory Status

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

Related Substances

—

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