Table II:
`
`Solubility of mannitol.
`
`Solvent
`
`Alkalis
`Ethanol (95%}
`Ether
`Glycerin
`Propan-2-ol
`Water
`
`Solubility at 20°c
`
`Soluble
`1 in 83
`Practically insoluble
`1 in 18
`1 in 100
`1 in 5.5
`
`100
`
`90
`
`80
`
`z
`...c 70
`0)
`C: i 60
`"'
`Cl)
`C: 50
`...c
`"' ::::, u 40
`ai
`:::c 30
`~
`
`20
`
`10
`
`Figure 1:
`
`Mannitol
`
`375
`
`copper, and iron. Reducing sugar impurities in mannitol have
`been implicated in the oxidative degradation of a peptide in a
`lyophilized formation. (25
`) Mannitol was found to reduce the
`oral bioavailability of cimetidine compared to sucroseY6l
`
`13 Method of Manufacture
`Mannitol may be extracted from the dried sap of manna and
`other natural sources by means of hot alcohol or other selective
`solvents. It is commercially produced by the catalytic or
`electrolytic reduction of monosaccharides such as mannose
`and glucose.
`
`12 . - - - - - - - - - - - - - - - - - - - - ,
`
`10 -
`
`8
`
`6
`
`~
`c
`2
`C:
`0 u
`~
`::::,
`
`-:;; ·o 4
`:E
`
`100
`
`10 20 30 40 50 60 70 80 90
`Compression force (kN)
`Compression characteristics of granular mannitol
`(Pear/ital, Roquette Freres}.
`O : Pearlitol 300DC
`D: Pear/ital 400DC
`6, : Pear/ital 500DC
`Tablet diameter: 20 mm
`Lubricant: magnesium stearate 0.7% w/w for Pear/ital
`400DC and Pear/ital 500DC; magnesium stearate l %
`w/w for Pear/ital 300DC.
`
`2
`
`Figure 2:
`
`67
`57
`Relative humidity (%)
`Sorption-desorption isotherm for mannitol.
`♦ : Sorption equilibrium moisture
`■ : Desorption equilibrium moisture
`
`75
`
`100
`
`100 . - - - - - - - - - - - - - - - - - - - ,
`
`11 Stability and Storage Conditions
`Mannitol is stable in the dry state and in aqueous solutions.
`Solutions may be sterilized by filtration or by autoclaving and
`if necessary may be autoclaved repeatedly with no adverse
`physical or chemical effectsY 2
`) In solution, mannitol is not
`attacked by cold, dilute acids or alkalis, nor by atmospheric
`oxygen in the absence of catalysts. Mannitol does not undergo
`Maillard reactions.
`The bulk material should be stored in a well-closed con(cid:173)
`tainer in a cool, dry place.
`
`Incompatibilities
`12
`Mannitol solutions, 20% w/v or stronger, may be salted out by
`potassium chloride or sodium chlorideY3
`) Precipitation has
`been reported to occur when a 25% w/v mannitol solution was
`allowed to contact plasticY4
`) Sodium cephapirin at 2 mg/mL
`and 30 mg/mL is incompatible with 20% w/v aqueou
`tol solution. Mannitol is incompatible with xylitol
`and may form complexes with some metals such as aluminum,
`
`80
`
`~
`Ql
`
`~ 60
`ai
`>
`0
`:c
`~ 40
`
`Cl)
`
`Median size = 88 µm
`
`20
`
`Figure 3:
`
`Particle size distribution of mannitol powder.
`
`60
`
`200
`
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`
`

`

`376
`
`Mannitol
`
`14 Safety
`Mannitol is a naturally occurring sugar alcohol found in
`animals and plants; it is present in small quantities in almost
`all vegetables. Laxative effects mai occur if mannitol is
`consumed orally in large quantities.< 7
`) If it is used in foods
`as a bodying agent and daily ingestion of over 20 g is foresee(cid:173)
`able, the product label should bear the statement 'excessive
`consumption may have a laxative effect'. After intravenous
`injection, mannitol is not metabolized to any appreciable
`extent and is minimally reabsorbed by the renal tubule
`about 80% of a dose being excreted in the urine in 3 hours. <2sl
`A number of adverse reactions to mannitol have been
`reported, primarily following the therapeutic use of 20% w/v
`aqueous intravenous infusions. (29
`) The quantity of mannitol
`used as an excipient is considerably less than that used
`therapeutically and is consequently associated with a lower
`incidence of adverse reactions. However, allergic, hypersensi(cid:173)
`tive-type reactions may occur when mannitol is used as an
`excipient.
`An acceptable daily intake of mannitol has not been
`specified by the WHO since the amount consumed as a
`sweetening agent was not considered to represent a hazard to
`health. <30l
`LD50 (mouse, IP): 14 g/kg(3 t)
`LD50 (mouse, IV): 7.47g/kg
`LD50 (mouse, oral): 22g/kg
`LD50 (rat, IV): 9.69 g/kg
`LD50 (rat, oral): 13.5 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Mannitol may be irritant to
`the eyes; eye protection is recommended.
`
`16 Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Guide (IP, IM, IV,
`and SC injections; infusions; buccal, oral and sublingual tablets
`and capsules). Included in nonparenteral and parenteral med(cid:173)
`icines licensed in the UK.
`
`17 Related Substances
`Sorbitol.
`
`18 Comments
`Mannitol is an isomer of sorbitol, the difference between the
`two polyols occurring in the planar orientation of the OH
`group on the second carbon atom. Each isomer is characterized
`by its own individual set of properties, the most important
`difference being the response to moisture. Sorbitol is hygro(cid:173)
`scopic, while mannitol resists moisture sorption, even at high
`relative humidities.
`Granular mannitol flows well and imparts improved flow
`properties to other materials. However, it usually cannot be
`used with concentrations of other materials exceeding 25% by
`weight. Recommended levels of lubricant are 1 % w/w calcium
`stearate or 1-2 % w/w magnesium stearate. Suitable binders for
`preparing granulations of powdered mannitol are
`methylcellulose 400, starch paste, povidone, and s
`Usually, 3-6 times as much magnesium stearate or 1.5-3
`
`times as much calcium stearate is needed for lubrication of
`mannitol granulations than is needed for other excipients.
`32)
`Mannitol has been reported to sublime at 130°C. <
`The EINECS number for mannitol is 200-711-8.
`
`19 Specific References
`1 Allen L V. Featured excipient: capsule and tablet diluents. Int J
`Phann Compound 2000; 4(4): 306-310, 324-325.
`2 Kanig JL. Properties of fused mannitol in compressed tablets. J
`Phann Sci 1964; 53: 188-192.
`3 Ward DR, Lathrop LB, Lynch MJ. Dissolution and compatibility
`considerations for the use of mannitol in solid dosage forms. J
`Pharm Sci 1969; 58: 1464-1467.
`4 Ghanem AH, Sakr FM, Abdel-Ghany G. Mechanical and
`physical properties of sulfamethoxazole-mannitol solid disper(cid:173)
`sion in tablet form. Acta Phann Fenn 1986; 95: 167-172.
`5 Debord B, Lefebvre C, Guyot-Hermann AM, et al. Study of
`different crystalline forms of mannitol: comparative behaviour
`under compression. Drug Dev Ind Pharm 1987; 13: 1533-1546.
`6 Molokhia AM, Al-Shara HI, Hammad AA. Aging of tablets
`prepared by direct compression of bases with different moisture
`content. Drug Dev Ind Pharm 1987; 13: 1933-1946.
`7 Mendes RW, Goll S, An CQ. Wet granulation: a comparison of
`Manni-Tab and mannitol. Drug Cosmet Ind 1978; 122(3): 36,
`38, 40, 44, 87-88.
`8 Daoust RG, Lynch MJ. MannitQl in chewable tablets. Drug
`Cosmet Ind 1963; 93(1): 26-28, 88, 92, 128-129.
`9 Herman J, Remon JP. Aluminium-magnesium hydroxide tablets:
`effect of processing and composition of granulating solution on
`the granule properties and in vitro antacid performance. Drug
`Dev Ind Phann 1988; 14: 1221-1234.
`10 Courie! B. Advances in lyophilization technology. Bull Parenter
`Drug Assoc 1977; 31: 227-236.
`11 Williams NA, Lee Y, Polli GP, Jennings TA. The effects of
`cooling rate on solid phase transitions and associated vial
`breakage occurring in frozen mannitol solutions. J Parenter Sci
`Technol 1986; 40: 135-141.
`.
`12 Stella VJ, Umprayn K, Waugh WN. Development of parenteral
`formulations of experimental cytotoxic agents I: rhizoxin (NSC-
`332598). Int J Pharm 1988; 43: 191-199.
`13 Williams NA, Dean T. Vial breakage by frozen mannitol
`solutions: correlation with thermal characteristics and effect of
`stereoisomerism, additives, and vial configuration. J Parenter Sci
`.Technol 1991; 45: 94-100.
`14 Chan HK, Au-Yeung KL, Gonda I. Development of a mathe(cid:173)
`matical model for the water distribution in freeze-dried solids.
`Pharm Res 1999; 16(5): 660-665.
`15 Pyne A, Surana R, Suryanarayanan R. Crystallization of
`mannitol below Tg' during freeze-drying in binary and ternary
`aqueous systems. Pharm Res 2002; 19: 901-908.
`16 Cavatur RK, Vemuri NM, Pyne A, et al. Crystallization behavior
`of mannitol in frozen aqueous solutions. Pharm Res 2002; 19:
`894-900.
`Izutsu K-I, Kojima S. Excipient crystallinity and its protein(cid:173)
`structure-stabilizing effect during freeze-drying. J Phann Phar(cid:173)
`macol 2002; 54: 1033-1039.
`·
`"'18 Parah PV, Oh CK, Ritschel WA. Sustained release from Precirol
`(glycerol palmito-stearate) matrix. Effect of mannitol and
`hydroxypropyl methylcellulose on the release of theophylline.
`Drug Dev Ind Pharm 1986; 12: 1309-1327.
`19 Tee SK, Marriott C, Zeng XM, Martin GP. Use of different
`sugars as fine and coarse carriers for aerosolised salbutamol
`sulphate. Int J Pf,ann 2000; 208: 111-123.
`20 Bauer H, Herkert T, Bartels M, et al. Investigations on
`polymorphism of mannitol/sorbitol mixtures after spray drying
`using differential scanning calorimetry, x-ray diffraction and
`near infrared spectroscopy. Pharm Ind 2000; 62(3): 231-235.
`21 Roquette Freres. Technical literature: Pearlitol, 1997.
`ction (25%)
`75; 32: 826-
`
`17
`
`827.
`
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`
`

`

`23
`
`Jacobs J. Factors influencing drug stability in intravenous
`infusions. J Hosp Pharm 1969; 27: 341-347.
`24 Epperson E. Mannitol crystallization in plastic containers
`[letter]. Am J Hosp Pharm 1978; 35: 1337.
`25 Dubost DC, Kaufman MJ, Zimmerman JA, et al. Characteriza(cid:173)
`tion of a solid state reaction product from a lyophilized
`formulation of a cyclic heptapeptide. A novel example of an
`excipient-induced oxidation. Pharm Res 1996; 13: 1811-1814.
`26 Adkin DA, Davis SS, Sparrow RA, et al. The effect of mannitol
`on the oral bioavailability of cimetidine. J Pharm Sci 1995; 84:
`1405-1409.
`.
`27 Anonymous. Flatulence, diarrhoea, and polyol sweeteners.
`Lancet 1983; ii: 1321.
`·-
`28 Porter GA, Starr A, Kimsey J, Lenertz H. Mannitol hemodilu(cid:173)
`tion--perfusion: the kinetics of mannitol distribution and excre(cid:173)
`tion during cardiopulmonary bypass. J Surg Res 1967; 7: 447-
`456.
`29 McNeill IY. Hypersensitivity reaction to mannitol. Drug Intel/
`Clin Pharm 1985; 19: 552-553.
`30 FAO/WHO. Evaluation· of certain food additives and contami(cid:173)
`nants. Thirtieth report of the joint FAO/WHO expert committee
`on food additives. World Health Organ Tech Rep Ser 19.87; No.
`751.
`
`Mannitol
`
`377
`
`31 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials,
`10th edn. New York: Wiley, 2000: 1952.
`32 Weast RC, ed. Handbook of Chemistry and Physics, 60th edn.
`Boca Raton: CRC Press, 1979: c-369.
`
`20 General References
`Czeisler JL, Perlman KP. Diluents. In: Swarbrick J, Boylan JC, eds.
`Encyclopedia of Pharmaceutical Technology, vol. 4. New York:
`Marcel Dekker, 1988: 37-84.
`
`21 Author
`NA Armstrong.
`
`22 Date of Revision
`22 October 2002.
`
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`
`

`

`Propylene Glycol
`
`a
`
`~
`
`.J£tt:,$!.,-,5,~""""'"""""'""!J
`
`!II
`
`™™'™''"""'£\,,,"Jm,,,¥JW , ma
`
`-
`
`1 Nonproprietary Names
`BP: Propylene glycol
`JP: Propylene glycol
`PhEur: Propylenglycolum
`USP: Propylene glycol
`
`2 Synonyms
`1,2-Dihydroxypropane; E1520; 2-hydroxypropanol; methyl
`ethylene glycol; methyl glycol; propane-1,2-diol.
`
`3 Chemical Name and CAS Registry Number
`1,2-Propanediol [57-55-6]
`(-)-1,2-Propanediol [4254-14-2]
`( + )-1,2-Propanediol [4254-15-3]
`
`4 Empirical Formula
`
`C3Hs02
`
`Molecular Weight
`76.09
`
`5 Structural Formula
`
`H-C-C-C-OH
`
`H
`
`I
`I
`
`H
`
`H
`
`I
`I
`
`H
`
`I
`I
`
`OH H
`
`6 Functional Category
`~
`Antimicrobial preservative; disinfectant; humectant; plastici(cid:173)
`zer; solvent; stabilizer for vitamins; water-miscible cosolvent.
`
`<
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Propylene glycol has become widely used as a solvent, extrac(cid:173)
`tant, and preservative in a variety of parenteral and nonpar(cid:173)
`enteral pharmaceutical formulations. It is a better general
`solvent than glycerin and dissolves a wide variety of materi(cid:173)
`als, such as corticosteroids, phenols, sulfa drugs, barbiturates,
`vitamins (A and D), most alkaloids, and many local anes(cid:173)
`thetics.
`As an antiseptic it is similar to ethanol, and against molds it
`is similar to glycerin and only slightly less effective than
`ethanol.
`Propylene glycol is commonly used as a plastizer in aqueous
`film-coating formulations.
`Propylene glycol is also used in cosmetics and in the food
`industry as a carrier for emulsifiers and as a vehicle for flavors
`in preference to ethanol, since its lack of volatility provides a
`more uniform flavor. See Table I.
`
`Table I: Uses of propylene glycol.
`
`Use
`
`Dosage form
`
`Concentration {%)
`
`Humectant
`Preservative
`· 'Solvent or cosolvent
`
`Topicals
`Solutions, semisolids
`Aerosol solutions
`Oral solutions
`Parenterals
`Topicals
`
`;:::, 15
`15-30
`10-30
`10-25
`1 0-<>0
`5---80
`
`8 Description
`Propylene glycol is a clear, colorless, viscous, practically
`odorless liquid with a sweet, slightly acrid taste resembling
`that of glycerin.
`
`9 Pharmacopeial Specifications
`See Table IL
`
`Table II:
`
`Pharmacopeial specifications for propylene glycol.
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`USP 25
`
`+
`
`~0.007%
`~0.006%
`~5ppm
`+
`
`Identification
`+
`+
`-
`Appearance
`+
`1.035-1.040 1.035-1.040 1.035-1.037
`Specific gravity
`Acidity
`+
`+
`+
`~0.5%
`Water
`~0.2%
`~0.2%
`-
`Residue on ignition
`~0.005%
`~0.007%
`-
`Sulfated ash
`~0.01%
`-
`Chloride
`~0.007%
`-
`Sulfate
`~0.002%
`Heavy metals
`~5ppm
`~5ppm
`-
`-
`Organic volatile
`impurities
`-
`Refractive index
`Oxidizing substances -
`Reducing substances -
`Arsenic
`~2ppm
`Glycerin
`+
`Distilling range
`184-189°(
`-
`Assay
`
`l .431-1 .433
`+
`+
`
`-
`
`;,,99.5%
`
`10 Typical Properties
`Autoignition temperature: 371 °C
`Boiling point: 188 °C
`Density: 1.038 g/cm3 at 20 °C
`Flammability: upper limit, 12.6% v/v in air; lower limit, 2.6%
`v/v in air.
`Flash point: 99 °C (open cup)
`Heat of combustion: 1803.3 kJ/mol ( 431.0 kcal/mo!)
`Heat of vaporization: 705 .4 Jig (168.6 cal/g) at b.p.
`Melting point: - 59 °C
`Osmolarity: a 2.0% v/v aqueous solution is iso-osmotic with
`
`521
`
`MY
`
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`
`

`

`522
`
`Propylene Glycol
`
`Refractive index: nf,0 = 1.4324
`Specific rotation [a.]f,0:
`-15.0 ° (neat) for (R)-form
`+15.8 ° (neat) for (S)-form
`Solubility: miscible with acetone, chloroform, ethanol (95%),
`glycerin, and water; soluble at 1 in 6 parts of ether; not
`miscible with light mineral oil or fixed oils, but will dissolve
`some essential oils.
`Specific heat: 2.47 J/g (0.590 cal/g) at 20 °C
`Surface tension: 40.1 mN/m (40.1 dynes/cm) at 25 °C
`Vapor density (relative): 2.62 (air = 1)
`Vapor pressure: 9.33 Pa (0.07 mmHg) at 20 °C
`Viscosity (dynamic): 58.lmPas (58.lcP) at 20°C
`
`11 Stability and Storage Conditions
`At cool temperatures, propylene glycol is stable in a well(cid:173)
`closed container, but at high temperatures, in the open, it
`tends to oxidize, giving rise to products such as propionalde(cid:173)
`hyde, lactic acid, pyruvic acid, and acetic acid. Propylene
`glycol is chemically stable when mixed with ethanol (95%),
`glycerin, or water; aqueous solutions may be sterilized by
`autoclaving.
`Propylene glycol is hygroscopic and should be stored in a
`well-closed container, protected from light, in a cool, dry
`place.
`
`Incompatibilities
`12
`Propylene glycol is incompatible with oxidizing reagents such
`as potassium permanganate.
`
`13 Method of Manufacture
`Propylene is converted to chlorohydrin by chlorine water and
`hydrolyzed to 1,2-propylene oxide. With further hydrolysis,
`1,2-propylene oxide is converted to propylene glycol.
`
`14 Safety
`Propylene glycol is used in a wide variety of pharmaceutical
`formulations and is generally regarded as a relatively nontoxic
`material. It is also used extensively in foods and cosmetics.
`Probably as a consequence of its metabolism and excretion,
`propylene glycol is less toxic than other glycols. Propylene
`glycol is rapidly absorbed from the gastrointestinal tract; there
`is also evidence that it is absorbed topically when applied to
`damaged skin. It is extensively metabolized in the liver, mainly
`to lactic and pyruvic acids and is also excreted unchanged in
`the urine. (l,ll
`-
`In topical preparations, propylene glycol is regarded as
`minimally irritant, although iS is more irritant than glycerin.
`Some local irritation is produced upon application to mucous
`membranes or when it is us~d under occlusive conditions. (3)
`Parenteral administration may cause pain or irritation when
`used in high concentration.
`Propylene glycol is estimated to be one-third as intoxicating
`as ethanol, with administration of large volumes being asso(cid:173)
`ciated with adverse effects most commonly on the central
`nervous system, especially in neonates and children. (4-6)
`Other adverse reactions reported, though generally isolated,
`include: ototoxicity;(7) cardiovascular effects; seizures; and
`hyperosmolarity<B) and lactic acidosis, both of wh
`most frequently in patients with renal impairment.
`effects are more likely to occur following consumption of large
`
`quantities of propylene glycol or on adminstration to neonates,
`children under 4 years of age, pregnant women, and patients
`with hepatic or renal failure. Adverse events may also occur in
`patients treated with disulfiram or metronidazole. (9)
`On the basis of metabolic and toxicological data, the WHO
`has set an acceptable daill intake of propylene glycol at up to
`25 mg/kg body-weight.0° Formulations containing 35% pro(cid:173)
`pylene glycol can cause hemolysis in humans.
`In animal studies, there has been no evidence that propylene
`glycol is teratogenic or mutagenic. Rats can tolerate a repeated
`oral daily dose of up to 30 mUkg in the diet over 6 months,
`while the dog is unaffected by a repeated oral daily dose of
`2g/kg in the diet for 2 years.0 1)
`LDso (mouse, IP): 9.72g/kg(ll)
`LD50 (mouse, IV): 6.63 g/kg
`LD50 (mouse, oral): 22.0 g/kg
`LD 50 (mouse, SC): 17.34g/kg
`LD5o (rat, IM): 0.01 g/kg
`LD5o {rat, IP): 6.66 g/kg
`LD 50 (rat, IV): 6.42 g/kg
`LD50 (rat, oral): 0.02g/kg
`LD 50 (rat, SC): 22.5 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Propylene glycol should be
`handled in a well-ventilated environment; eye protection is
`recommended. In the UK, the long-term (8-hour TWA)
`occupational exposure limit for propylene glycol vapor and
`particulates is 474mg/m3 (150ppm) and 10mg/m3 for parti(cid:173)
`culates. (l 3 J
`
`16 Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Guide (dental pre(cid:173)
`parations, IM and IV injections, inhalations, ophthalmic, oral,
`otic, percutaneous, rectal, topical, and vaginal preparations).
`Included in non parenteral and parenteral medicines licensed in
`the UK.
`
`17 Related Substances
`
`18 Comments
`In addition to its uses as an excipient, propylene glycol is used
`in veterinary medicine as an oral glucogenic in ruminants. (l 4 )
`"Th~ EINECS number for propylene glycol is 200-338-0.
`
`19 Specific References
`1 Yu DK, Elmquist WF, Sawchuk RJ. Pharmacokinetics of
`propylene glycol in humans during multiple dosing regimens. J
`Phann Sci 1985; 74: 876-879.
`2 Speth PAJ, Vree TB, Neilen NF, et al. Propylene glycol
`pharmacokinetics and effects after intravenous infusion in
`humans. Ther Drug Monit 1987; 9: 255-258.
`3 Motoyoshi K, Nozawa S, Yoshimura M, Matsuda K. The safety
`of propylene glycol and other humectants. Cosmet Toilet 1984;
`99(10): 83-91.
`
`system toxicity
`diatr 1978; 93:
`
`515-516.
`
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`
`

`

`Propylene G/ycol
`
`523
`
`20 General References
`Doenicke A, Nebauer AE, Hoernecke R, et al. Osmolalities of
`propylene glycol-containing drug formulations for parenteral use:
`should propylene glycol be used as a solvent? Anesth Analg 1992;
`75(3): 431-435.
`Krzyzaniak JF, Raymond DM, Yalkowsky SH. Lysis of human red
`blood cells 2, effect of contact time on cosolvent induced
`hemolysis. Int J Pharm 1997; 152: 193-200.
`Wells JI, Bhatt DA, Khan KA. Improved wet massed tableting using
`plasticized binder. J Pharm Pharmacol 1982; 34{Suppl.}: 46P.
`Yu CD, Kent JS. Effect of propylene glycol on subcutaneous
`absorption of a bcnzimidazole hydrochloride. J Phann Sci 1982;
`•
`71: 476-478.
`
`5 MacDonald MG, Getson PR, Glasgow AM, et al. Propylene
`glycol: increased incidence of seizures in low birth weight infants.
`Pediatrics 1987; 79: 622-625.
`6 Martin G, Finberg L. Propylene glycol: a potentially toxic vehicle
`in liquid dosage form. J Pediatr 1970; 77: 877--S78.
`7 Morizono T, Johnstone BM. Ototoxicity of chloramphenicol ear
`drops with propylene glycol as solvent. Med J Aust 1975; 2: 634-
`638.
`8 Fligner CL, Jack R, Twiggs GA, Raisys VA. Hyperosmolality
`induced by propylene glycol: a complication of silver sulfadiazine
`therapy. J Am Med Assoc 1985; 253: 1606-1609.
`9 Anonymous. US warning on HIV drug excipient. Pharm J 2000;
`264: 685.
`10 FAO/WHO. Toxicological evaluation of certain food additives._
`with a review of general principles and of specifications. ~
`Seventeenth report of the FAO/WHO expert committee on food
`additives. World Health Organ Tech Rep Ser 1974: No. 539.
`11 Clayton GD, Clayton FE, eds. Patty's Industrial Hygiene and
`Toxicology, 3rd edn. Chichester: Wiley, 1987.
`12 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials,
`10th edn. New York: Wiley, 2000: 3061.
`13 Health and Safety Executive. EH40/2002: Occupational Expo(cid:173)
`sure Limits 2002. Sudbury: Health and Safety Executive, 2002.
`14 Bishop Y, ed. The Veterinary Formulary, 5th edn. London:
`Pharmaceutical Press, 2001: 551-552.
`
`21 Author
`PJ Weller.
`
`22 Date of Revision
`3 May 2002.
`
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`

`

`Sodium Phosphate, Dibasic
`
`8 Description
`The USP 25 states that dibasic sodium phosphate is dried or
`contains, 1, 2, 7, or 12 molecules of water of hydration.
`Anhydrous dibasic sodium phosphate occurs as a white
`powder. The dihydrate occurs as white or almost white,
`odorless crystals. The heptahydrate occurs as colorless crys(cid:173)
`tals or as a white granular or caked salt that effloresces in
`warm, dry air. The dodecahydrate occurs as strongly efflor(cid:173)
`escent, colorless or transparent crystals.
`
`9 Pharmacopeial Specifications
`See Table I.
`
`Table I:
`dibasic.
`
`Test
`
`Phormacopeial specifications for sodium phosphate,
`
`JP 2001
`
`PhEur 2002 USP 25
`
`1 Nonproprietary Names
`BP:
`Anhydrous disodium hydrogen phosphate
`Disodium hydrogen phosphate
`Disodium hydrogen phosphate dodecahydrate
`Dibasic sodium phosphate
`JP:
`PhEur: Dinatrii phosphas anhydricus
`Dinatrii phosphas dihydricus
`Dinatrii phosphas dodecahydricus
`Dibasic sodium phosphate
`USP:
`Note that the BP 2001 and PhEur 2002 contain three separate
`monographs for the anhydrous, the dihydrate, and the dodeca(cid:173)
`hydrate; the JP 2001 contains one monograph for the do(cid:173)
`decahydrate; and the USP 25 contains one monograph for
`the anhydrous, the monohydrate, the dihydrate, the hepta(cid:173)
`hydrate, and the dodecahydrate. See also Section 8.
`
`2 Synonyms
`Disodium hydrogen phosphate; disodium phosphate; E339;
`phosphoric acid, disodium salt; secondary sodium phosphate;
`sod ium orthophosphate.
`
`3 Chemical Name and CAS Registry Number
`Anhydrous dibasic sodium phosphate [7558-79-4]
`Dibasic sodium phosphate dihydrate [10028-24-7]
`Di basic sodium phosphate dodecahydrate [10039-32-4]
`Dibasic sodium phosphate heptahydrate [7782-85-6]
`Dibasic sodium phosphate hydrate [10140-65-5]
`Dibasic sodium phosphate monohydrate [118830-14-1]
`
`4 Empirical Formula
`Na2HPO4
`Na2HPO4-H2O
`Na2HPO4·2H2O
`Na2HPO4-7H2O
`Na2HPO4 -l2H2O
`
`Molecular Weight
`141.96
`159.94
`177.98
`268 .03
`358.08
`
`5 Structural Formula
`Na2HPO4-xH2O where x = 0, 1, 2, 7, or 12.
`
`6 Functional Category
`Buffering agent; sequestering agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Dibasic sodium phosphate is used in a wide variety of phar(cid:173)
`maceutical formu lations as a buffering agent and as a seques(cid:173)
`tering agent. Therapeutically, dibasic sodium phosphate is
`used as a mild laxative and in the treatment of hypo(cid:173)
`phosphatemia. (I ,Z)
`Dibasic sodi um phosphate is also used in food products; for
`example as an emulsifier in processed cheese.
`
`574
`
`Identification
`+
`Characters
`+
`Appearance of solution +
`pH
`9 .0-9.4
`Reducing substances
`Monosodium phosphate -
`Carbonate
`+
`Chloride
`,s:; 0 .014%
`Di hydrate
`Dodecahydrate
`Water
`Dihydrate
`Dodecahydrate
`Sulfates
`Di hydrate
`Dodecahydrate
`Arsenic
`Dihydrate
`Dodecahydrate
`Heavy metals
`Dihydrate
`Dodecahydrate
`Iron
`Di hydrate
`Dodecahydrate
`Loss on drying
`Anhydrous
`· Monohydrate
`Di hydrate
`Heptahydrate
`Dodecahydrate
`Assay (dried basis)
`
`,s:; 0 .038%
`
`,s:; 2ppm
`
`,s;; l0ppm
`
`+
`
`+
`+
`+
`
`+
`,s:; 0 .025%
`
`+
`,s:; 400ppm
`,s:; 200ppm
`+
`
`57 .0-o 1.0%
`
`,s:; 0.06%
`
`,s:; 0 .2%
`
`,s:; 16ppm
`
`,s:; 0 .002%
`
`+
`,;;; 5 .0%
`10.3-12.0%
`19.5-21.0% 18.5-21.5%
`43.0-50 .0%
`55 .0-64.0%
`98 .0-101 .0% 98 .0-100.5%
`
`,s:; 0 . 1%
`,s:; 500ppm
`+
`,s:; 4ppm
`,s:; 2ppm
`+
`,s:; 20ppm
`,;;; l0ppm
`+
`,s:; 40ppm
`,s:; 20ppm
`57.0--0 l .0% +
`
`;;, 98 .0%
`
`10 Typical Properties
`Acidity/ alkalinity: pH= 9.1 for a 1 % w/v aqueous solution of
`the anhydrous material at 25°C. A saturated aqueous
`solution of the dodecahydrate has a pH of about 9.5.
`
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`
`

`

`Ionization constants:( 3
`)
`pK. 1 = 2.15 at 25°C
`pK. 2 = 7.20 at 25°C
`pK.3 = 12.38 at 25°C
`Moisture content: the anhydrous form is hygroscopic and will
`absorb water on exposure to air, whereas the heptahydrate
`is stable in air.
`Osmolarity: a 2.23% w/v aqueous solution of the dihydrate is
`isoosmotic with serum; a 4.45% w/v aqueous solution of
`the dodecahydrate is isoosmotic with serum.
`Solubility: very soluble in water, more so in hot or boiling
`water; practically insoluble in ethanol (95% ). The an(cid:173)
`hydrous material is soluble 1 in 8 parts of water, the
`heptahydrate 1 in 4 parts of water, and the dodecahydrate
`1 in 3 parts of water.
`
`11 Stability and Storage Conditions
`The anhydrous form of dibasic sodium phosphate is hygro(cid:173)
`scopic. When heated to 40°C, the dodecahydrate fuses; at
`100°C it loses its water of crystallization; and at a dull-red
`heat (about 240°C) it is converted into the pyrophosphate,
`a4P2O 7 . Aqueous solutions of dibasic sodium phosphate are
`stable and may be sterilized by autoclaving.
`The bulk material should be stored in an airtight container,
`in a cool, dry place.
`
`Incompatibilities
`12
`Dibasic sodium phosphate is incompatible with alkaloids,
`antipyrine, chloral hydrate, lead acetate, pyro~allol, resorci(cid:173)
`nol and calcium gluconate, and ciprofloxacin. 4) Interaction
`between calcium and phosphate, leading to the formation of
`insoluble calcium-phosphate precipitates, is possible in par(cid:173)
`enteral admixtures.
`
`13 Method of Manufacture
`Either bone phosphate (bone ash), obtained by heating bones
`to whiteness, or the mineral phosphorite is used as a source of
`tribasic calcium phosphate, which is the starting material in the
`industrial production of dibasic sodium phosphate.
`Tribasic calcium phosphate is finely ground and digested
`with sulfuric acid. This mixture i then leached with hot water
`and neutralized with sodium carbonate, and dibasic sodium
`phosphate is crystallized from the filtrate.
`
`14 Safety
`Dibasic sodium phosphate is widely used as an excipient in
`parenteral, oral, and topical pharmaceutical formulations.
`Phosphate occurs extensively in the body and is involved in
`many physiological processes since it is the principal anion of
`intracellular fluid. Most foods contain adequate amounts of
`phosphate, making hypophosphatemia
`(phosphate defi(cid:173)
`ciencyf ) virtually unknown except for certain disease
`states( ) or in patients receiving total parenteral nutrition.
`Treatment is usually by the oral administration of up to
`100 mmol of phosphate daily.
`1s
`ingested phosphate
`two-thirds of
`Approximately
`absorbed from the gastrointestinal tract, virtually all of it
`being excreted in the urine, and the remainder is excreted in
`the feces.
`Excessive administration of phosphate, particularly intra(cid:173)
`venously, rectally, or in patients with renal failure, can cause
`
`Sodium Phosphate, Dibasic
`
`575
`
`hyperphosphatemia that may lead to hypocalcemia or other
`severe electrolyte imbalances.(5•6 ) Adverse effects occur less
`frequently following oral consumption, although phosphates
`act as mild saline laxatives when administered orally or
`rectally. Consequently, gastrointestinal disturbances includ(cid:173)
`ing diarrhea, nausea, and vomiting may occur following the
`use of dibasic sodium phosphate as an excipient in oral
`formulations. However, the level of di basic sodium phosphate
`used as an excipient in a pharmaceutical formulation is not
`usually associated with adverse effects.
`LDso (rat, oral): 17 g/kg(7
`
`)
`
`1 5 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Dibasic sodium phosphate
`may be irritating to the skin, eyes, and mucous membranes.
`Eye protection and gloves are recommended.
`
`16 Regulatory Status
`GRAS listed. Accepted in Europe as a food additive. Included
`in the FDA Inactive Ingredients Guide (injections; infusions;
`nasal, ophthalmic, oral, otic, topical, and vaginal prepara(cid:173)
`tions). Included in nonparenteral and parenteral medicines
`licensed in the UK.
`
`17 Related Substances
`Dibasic potassium phosphate; sodium phosphate, monobasic;
`tribasic sodium phosphate.
`
`Dibasic potassium phosphate
`Empirical formula: K2HPO4
`Molecular weight: 174.15
`CAS number: [7758-11-4]
`Synonyms: dipotassium hydrogen orthophosphate; dipotas(cid:173)
`sium hydrogen phosphate; dipotassium phosphate; E340;
`potassium phosphate.
`Appearance: colorless or white, granular, hygroscopic powder.
`Acidity/alkalinity: pH = 8.5-9.6 for a 5% w/v aqueous solu(cid:173)
`tion at 25°C.
`Osmolarity: a 2.08% w/v aqueous solution of dibasic potas(cid:173)
`sium phosphate is isoosmotic with serum.
`Solubility: freely soluble in water; very slightly soluble in
`ethanol (95 % ).
`Comments: one gram of dibasic potassium phosphate contains
`approximately ll.5mmol of potassium and 5.7mmol of
`phosphate.
`
`Tribasic sodium phosphate
`Empirical formula: Na3PO4·XH2O
`Molecular weight:
`163.94 for the anhydrous material
`380.06 for the dodecahydrate (12H2O)
`CAS number: [7601-54-9] for the anhydrous material.
`Synonyms: E339; trisodium orthophosphate; trisodium phos(cid:173)
`phate; TSP.
`Acidity/alkalinity: pH= 12.1 for a 1 % w/v aqueous solution of
`the anhydrous material at 25°C. A 1 % w/v aqueous solu(cid:173)
`tion of the dodecahydrate at 25°C has a pH of 12.0-12.2.
`Density:
`1.3 g/cm3 for the anhydrous material
`0.9 g/cm3 for the dodecahydrate
`
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`

`576
`
`Sodium Phosphate, Dibasic
`
`Solubility: the anhydrous material is soluble 1 in 8 parts of
`water, while the dodecahydrate is soluble 1 in 5 parts of
`water at 20°C.
`
`18 Comments
`One gram of anhydrous dibasic sodium phosphate represents
`approximately 14.lmmol of sodium and 7.0mmol of phos(cid:173)
`phate.
`One gram of dibasic sodium phosphate dihydrate repre(cid:173)
`sents approximately 11.2 mmol of sodium and 5.6 mmol of
`phosphate.
`One gram of dibasic sodium phosphate heptahydrate
`represents approximately 7.5 mmol of sodium and 3. 7 mmol
`of phosphate.
`One gram of dibasic sodium phosphate dodecahydrate
`represents approximately 5.6 mmol of sodium and 2.8 mmol
`of phosphate.
`
`19 Specific References
`1 Lloyd CW, Johnson CE. Management of hypophosphatemia. Clin
`Pharm 1988; 7: 123-128.
`2 Holland PC, Wilkinson AR, Diez ], Lindsell DRM. Prenatal
`deficiency of phosphate, phosphate supplementation, and rickets
`in very-low-birthweight infants. Lancet 1990; 335: 697-701.
`
`3 Albert A, Serjearnt EP. Ionization Constants of Acids and Bases,
`2nd edn. Edinburgh: Chapman and Hall, 1971.
`4 Benjamin BE. Ciprofloxacin and sodium phosphates not compa(cid:173)
`tible during actual Y-site injec