W Water 76 7

Water

40.05 mg/L

41.0 mg
purified
Sterile

water
JP XV

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for containers
425 mS/cm for

45 mS/cm
containers

<0.25 IU/mL
410 mL,

510 ml
40.2 ppm
40.2 ppm
PhEur 6.3

410 ppb
water for
injection
1 Nonproprietary Names purified water, water for injection (WFI), sterile water for injection,

Sterile

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BP: Purified Water bacteriostatic water for injection, sterile water for irrigation, or

40.25 IU/mL
sterile water for inhalation. Validation is required for all systems

40.5 mg/L
40.2 ppm
JP: Purified Water

PhEur 6.3

410 ppb
Water for
injection
(in bulk)
producing the water indicated, with the exception of potable water.
PhEur: Water, Purified

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The chemical composition of potable water is variable, and the

40.25 EU/mL

(a) For water for injection preserved in containers and sterilized, the JP XV provides separate tests for acid or alkali, chloride, ammonium, and residue on evaporation within the monograph.
USP: Purified Water nature and concentrations of the impurities in it depend upon the

Water for
injection
USP 32
See also Sections 8 and 17. source from which it is drawn. Water classified as potable water for

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applications such as some initial rinsing and API manufacturing

40.25 EU/mL
2 Synonyms operations, must meet the US Environmental Protection Agency’s

injection(a)
Water for
National Primary Drinking Water Regulations, or comparable

JP XV
Aqua; aqua purificata; hydrogen oxide.

þ(b)
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regulations of the EU or Japan. For most pharmaceutical applica-

45 mS/cm for
for containers
tions, potable water is purified by distillation, ion exchange

containers
410 mL,
425 mS/cm
3 Chemical Name and CAS Registry Number

510 ml
treatment, reverse osmosis (RO), or some other suitable process

purified

USP 32
Sterile

water
Water [7732-18-5] to produce ‘purified water’. For certain applications, water with

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pharmacopeial specifications differing from those of purified water

for containers
425 mS/cm for

40.25 EU/mL
45 mS/cm
4 Empirical Formula and Molecular Weight

containers
should be used, e.g. WFI; see Sections 9 and 18.

410 mL,

510 ml
water for
irrigation
Water is a clear, colorless, odorless, and tasteless liquid.

USP 32
H2 O 18.02

Sterile

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for containers
425 mS/cm for

45 mS/cm
containers
5 Structural Formula

<0.5 EU/mL
410 mL,

510 ml
inhalation
water for

USP 32
Sterile
See Section 4. 9 Pharmacopeial Specifications

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See Table II. See also Section 17.

Bacteriostatic

<0.5 EU/mL
6 Functional Category

water for

4.5–7.0
injection
USP 32
Solvent.

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

40.25 EU/mL
water for

5.0–7.0
injection
7 Applications in Pharmaceutical Formulation or 10 Typical Properties

USP 32
Sterile
Technology

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Boiling point 1008C

40.25 IU/mL
Water is widely used as a raw material, ingredient and solvent in the Critical pressure 22.1 MPa (218.3 atm)

40.5 mg/L
40.2 ppm
PhEur 6.3

410 ppb
USP 32 purified
processing, formulation and manufacture of pharmaceutical Critical temperature 374.28C

Purified Water,
water highly
Dielectric constant D 25 = 78.54

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products, active pharmaceutical ingredients (API) and intermedi-
ates, and analytical reagents. Specific grades of water are used for Dipole moment

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particular applications in concentrations up to 100%; see Table I. 1.76 in benzene at 258C;

4102 cfu/mL

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

40.2 ppm

40.001%
containers
PhEur 6.3
1.86 in dioxane at 258C.

water in
Purified
Table I: Typical applications of specific grades of water. Ionization constant 1.008  1014 at 258C.
W

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40.25 IU/mL
Latent heat of fusion 6 kJ/mol (1.436 kcal/mol)

40.2 ppm

40.1 ppm
Type Use

PhEur 6.3

410 ppb
water in
Latent heat of vaporization 40.7 kJ/mol (9.717 kcal/mol)

Purified

bulk
Bacteriostatic water for injection Diluent for ophthalmic and multiple- Melting point 08C

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dose injections. Refractive index n20 D = 1.3330

40.05 mg/L
Potable water Public supply suitable for drinking,

41.0 mg
Solubility Miscible with most polar solvents.

Purified
water
JP XV
the purity of which is unlikely to be
Specific gravity 0.9971 at 258C.

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suitable for use in the manufacture

40.05 mg/L
of pharmaceuticals. Specific heat (liquid) 4.184 J/g/8C (1.00 cal/g/8C) at 148C.
Surface tension 71.97 mN/m (71.97 dynes/cm) at 258C.

Water
JP XV
Purified water Vehicle and solvent for the

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manufacture of drug products and Vapor pressure 3.17 kPa (23.76 mmHg) at 258C.
W Viscosity (dynamic) 0.89 mPa s (0.89 cP) at 258C.

Microbial contamination
pharmaceutical preparations; not

reducing substances
Residue on evaporation
Appearance of solution

Oxidizable substances
Nitrogen from nitrate

Total organic carbon

Antimicrobial agents
Nitrogen from nitrite

Bacterial endotoxins
suitable for use in the manufacture

Anionic surfactants

Extractable volume
permanganate-

Particulate matter
Carbon dioxide
Odor and taste
of parenteral products.

Total hardness
Acid or alkali

Heavy metals
Identification

Conductivity
Magnesium
Ammonium
Characters
Production
Sterile water for inhalation Diluent for inhalation therapy

Aluminum

Potassium
Cadmium
Chloride
Cyanide

Calcium
Copper

Sterility
Nitrate
Sulfate
products.

Lead
Iron
Test
11 Stability and Storage Conditions

pH
Sterile water for injection Diluent for injections.
Sterile water for irrigation Diluent for internal irrigation therapy Water is chemically stable in all physical states (ice, liquid, and
products. vapor). Water leaving the pharmaceutical purification system and
Water for injections in bulk Water for the bulk preparation of entering the storage tank must meet specific requirements. The goal
medicines for parenteral
when designing and operating the storage and distribution system is
administration.
to keep the water from exceeding allowable limits during storage. In
particular, the storage and distribution system must ensure that
water is protected against ionic and organic contamination, which
8 Description would lead to an increase in conductivity and total organic carbon,
The term ‘water’ is used to describe potable water that is freshly respectively. The system must also be protected against physical
drawn direct from the public supply and is suitable for drinking. entry of foreign particles and microorganisms so that microbial
Water used in the pharmaceutical industry and related disciplines is growth is prevented or minimized. Water for specific purposes
classified as either drinking (potable) water, purified water, sterile should be stored in appropriate containers; see Table III.

7 66
 7 68 Water Water 76 9

Table III: Storage requirements for different grades of water. exchange, RO or any other suitable method that complies with 14 Safety Sterile water for irrigation
regulations on water intended for human consumption laid down Water is the base for many biological life forms, and its safety in Comments The USP 32 describes sterile water for irrigation as
Type Storage requirements(a) by the competent authority. The USP 32 and the JP XV permit the pharmaceutical formulations is unquestioned provided it meets WFI sterilized and suitably packaged. It contains no antimicro-
Bacteriostatic water for injection Preserve in single-dose and multiple-
use of RO in addition to distillation and ultrafiltration. In the past standards of quality for potability(9) and microbial content; see bial agents or other substances.
dose containers, preferably of 10–15 years, RO has become the most common way to produce Sections 9 and 18. Plain water is considered slightly more toxic Water for injection (WFI)
Type I or Type II glass, not larger pharmaceutical purified water, either as a final treatment step or as a
upon injection into laboratory animals than physiological salt Comments The USP 32 describes WFI as water purified by
than 30 mL in size. pretreatment step for the distillation stills.
solutions such as normal saline or Ringer’s solution. distillation or RO. It contains no added substances. The PhEur
Potable water Preserve in tightly sealed containers. Distillation Distillation is a process that involves the evaporation
Purified water Preserve in tightly sealed containers. of water followed by the condensation of the resulting steam.
Ingestion of excessive quantities of water can lead to water 6.3 title is ‘water for injections’ and comprises two parts: ‘water
If it is stored in bulk, the conditions While expensive, it allows removal of almost all organic and intoxication, with disturbances of the electrolyte balance. for injections in bulk’ and ‘sterilized water for injection’. The
of storage should be designed to inorganic impurities and achieves very high quality water. It is WFI should be free from pyrogens. PhEur 6.3 states that water for injections is produced by
limit the growth of microorganisms distillation.
and avoid any other also considered the safest method to avoid microbial and LD50 (mouse, IP): 25 g/kg(10)
contamination. endotoxin contamination. To improve energy efficiency, distilla-
Sterile water for inhalation Preserve in single-dose containers, tion is usually conducted in multiple-effects stills designed to 18 Comments
preferably of Type I or Type II recover most of the energy spent on evaporating the water. A 15 Handling Precautions
glass. typical design consists of an evaporator, vapor separator, and In most pharmacopeias, the term ‘water’ now refers to purified or
Sterile water for injection Preserve in single-dose containers,
Observe normal precautions appropriate to the circumstances and distilled water.
compressor. The distilland (raw feed water) is heated in the quantity of material handled.
preferably of Type I or Type II evaporator to boiling and the vapor produced is separated from Without further purification, ‘water’ may be unsuitable for
glass, not more than 1000 mL in certain pharmaceutical applications; for example, the presence of
entrained distilland in the separator. The vapor then enters a
size. calcium in water affects the viscosity and gel strength of algins and
Water for injection Preserve in tightly sealed containers. compressor where the temperature of the vapors is raised to 16 Regulatory Status
Water for injections in bulk Collect and store in conditions 1078C. Superheated vapors are then condensed on the outer pectin dispersions, while the use of potable water affects the clarity
surface of the tubes of the evaporator containing cool distilland Included in nonparenteral and parenteral medicines licensed in the and quality of cough mixtures, and the stability of antibiotic liquid
designed to prevent growth of
microorganisms and avoid any circulating within. UK and USA. preparations.
other contamination. Vapor compression stills of various sizes are commercially Water commonly contains salts of aluminum, calcium, iron,
available and can be used to produce water of high purity when magnesium, potassium, sodium, and zinc. Toxic substances such as
(a) To prevent evaporation and to maintain quality.
properly constructed. A high-quality distillate, such as WFI, can 17 Related Substances arsenic, barium, cadmium, chromium, cyanide, lead, mercury, and
be obtained if the water is first deionized. The best stills are Bacteriostatic water for injection; carbon dioxide-free water; de- selenium may constitute a danger to health if present in excessive
constructed from types 304 or 316 stainless steel and coated with aerated water; hard water; soft water; sterile water for inhalation; amounts. Ingestion of water containing high amounts of calcium
12 Incompatibilities pure tin, or are made from chemical-resistant glass. sterile water for injection; sterile water for irrigation; water for and nitrate is also contraindicated. National standards generally
In pharmaceutical formulations, water can react with drugs and Deionization An ionic exchange process is based on the ability of injection (WFI). specify the maximum limits for these inorganic substances in
other excipients that are susceptible to hydrolysis (decomposition in certain synthetic resins to selectively adsorb either cations or potable water. Limits have also been placed on microorganisms,
the presence of water or moisture) at ambient and elevated Bacteriostatic water for injection
anions, and to release (exchange) other ions based on their detergents, phenolics, chlorinated phenolics, and other organic
temperatures. Comments The USP 32 describes bacteriostatic water for injection
relative activity. Cationic and anionic ion exchange resins are substances. The WHO(11) and national bodies have issued guide-
Water can react violently with alkali metals and rapidly with used to purify potable water by removing any dissolved ions. as sterile water for injection that contains one or more suitable
antimicrobial agents. lines for water quality, although many countries have their own
alkaline metals and their oxides, such as calcium oxide and Dissolved gases are also removed, while chlorine, in the standards for water quality embodied in specific legislation.(12) See
magnesium oxide. Water also reacts with anhydrous salts to form concentrations generally found in potable water, is destroyed Carbon dioxide-free water Table IV.
hydrates of various compositions, and with certain organic by the resin itself. Some organics and colloidal particles are Comments Purified water that has been boiled vigorously for 5
materials and calcium carbide. removed by adsorption and filtration. Resin beds may, however, minutes and allowed to cool while protecting it from absorption
foster microbial life and produce pyrogenic effluent unless of atmospheric carbon dioxide. Table IV: Limits for inorganic substances in potable water (mg/L).
13 Method of Manufacture adequate precautions are taken to prevent contamination.
Another disadvantage is the type of chemicals required for resin De-aerated water Contaminant UK (mg/L) WHO (mg/L)
Unlike other excipients, water is not purchased from outside Comments Purified water that has been boiled vigorously for 5
suppliers but is manufactured in-house by pharmaceutical compa- regeneration. A continuous deionization system, which repre- Aluminum 0.2 0.2
sents a combination of ion exchange and membrane separation minutes and cooled to reduce the air (oxygen) content. Ammonium 0.5 —
nies. As naturally occurring water has a variety of contaminants, Antimony 0.01 —
many treatment processes have been developed to remove these. A technologies, uses an electrical current to continuously regener- Hard water
Arsenic 0.05 0.05
typical pharmaceutical water purification system contains several ate the ion exchange resin simultaneously with the water Comments Water containing the equivalent of not less than Barium 1.0 No limit
unit operations designed to remove various components. The treatment process, eliminating the need to handle powerful 120 mg/L and not more than 180 mg/L of calcium carbonate. Beryllium — No limit
selection of the most appropriate system and its overall design are chemicals. Ion exchange units are normally used today to treat Boron 2.0 —
raw feed water prior to distillation or RO processing. Soft water
crucial factors in ensuring that water of the correct quality is Cadmium 0.005 0.005
Reverse osmosis Water is forced through a semipermeable Comments Water containing the equivalent of not more than
produced.(1,2) 60 mg/L of calcium carbonate.
Calcium 250 —
To produce potable or drinking water, insoluble matter is first membrane in the opposite direction to normal osmotic diffusion. Chloride 400 250

W removed from a water supply by coagulation, settling (clarifica-

tion), and filtering processes. Pathogenic microorganisms present
Typically, membranes range between 1–10 Å and reject not only
organic compounds, bacteria and viruses, but also 90–99% of
Sterile water for inhalation
Comments The USP 32 describes sterile water for inhalation as
Chromium
Copper
Cyanide
0.05
3.0
0.05
0.05
1.0
0.1
are then destroyed by aeration, chlorination, or some other means. all ions. It is common to use double-pass RO systems with two WFI sterilized and suitably packaged. It contains no antimicro- Fluoride 1.5 1.5
Water may also be rendered free of viable pathogenic microorgan- filtration stages connected in series. Such systems meet require- bial agents or other added substances, except where used in Iron 0.2 0.3
isms by active boiling for 15–20 minutes. Activated carbon filters ments for USP purified water and WFI. However, EU regulations humidifiers or other similar devices, and where liable to Lead 0.05 0.05
are employed to remove chlorine and many dissolved organic do not allow RO to be used as a final treatment step for the contamination over a period of time. Magnesium 50 —
materials found in water, although they may become a breeding production of WFI. Manganese 0.05 0.1
ground for microorganisms. The palatability of the water is Membrane filtration Membrane filters are surface-type filters, Sterile water for injection Mercury 0.001 0.001
improved by aeration and charcoal filtration. which stop particles larger than the pore size at the upstream Comments The USP 32 describes sterile water for injection as WFI Nickel 0.05 No limit
surface of the polymeric membrane. Microfiltration uses sterilized and suitably packaged. It contains no antimicrobial Nitrate (as N) — 10
Purified water suitable for use in pharmaceutical formulations is
agents or other substances. Nitrate (as NO3) 50 —
usually prepared by purifying potable water by one of several membranes with pores in the 0.1–1.0 mm range, which can filter
Sterile water for injection in containers is one of the materials Nitrite (as NO2) 0.1 —
processes, such as distillation, deionization, or RO.(1,3–8) out particles of dust, activated carbon, ion exchange resin fines, Phosphorus 2.2 —
The quality attributes of WFI are stricter than those for purified and most microorganisms. Ultrafiltration uses membranes that that have been selected for harmonization by the Pharmacopeial Potassium 12 —
water. Consequently, the preparation methods typically vary in the reject not only solid particles but also dissolved matter with a Discussion Group. For further information see the General Selenium 0.01 0.01
last stage to ensure good control of WFI quality. Methods for the high molecular weight. The ‘molecular weight cut-off’ point of Information Chapter <1196> in the USP32–NF27, the General Silver 0.01 No limit
production of WFI are the subject of current debate. The PhEur 6.3 such membranes varies in the range 10 000–100 000 Da, and Chapter 5.8 in PhEur 6.0, along with the ‘State of Work’ Sodium 150 200
indicates that only distillation would give assurance of consistent bacteria, endotoxins, colloidal contaminants, and large organic document on the PhEur EDQM website, and also the General Sulfate 250 400
supply of the appropriate quality, but permits distillation, ion molecules can be removed. Information Chapter 8 in the JP XV. Zinc 5.0 5.0