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Imidurea is compatible with other preservatives including sorbic acid and quaternary ammonium compounds.(5) It is also compatible with other pharmaceutical and cosmetic excipients including proteins, nonionic surfactants, and lecithin.(6)

360 Imidurea

Table III: Solubility of imidurea.

Solvent Solubility at 208C

Ethanol Very slightly soluble

Ethanol (90%) Very slightly soluble

Ethanol (70%) 1 in 330

Ethanol (60%) 1 in 25

Ethanol (50%) 1 in 2.5

Ethanol (30%) 1 in 0.8

Ethylene glycol(a) 1 in 0.7

Glycerin(a) 1 in 1

Appearance: white, free-flowing hygroscopic powder, with a faint characteristic odor.

Antimicrobial activity: similar to imidurea.(13,14) Diazolidinyl urea is the most active of the imidazolidinyl family of preservatives. Used in concentrations of 0.1–0.5% w/w, at pH 3–9, it has predominantly antibacterial properties. Typical MICs are: Aspergillus niger 4000 mg/mL; Candida albicans 8000 mg/mL; Escherichia coli 1000 mg/mL; Pseudo- monas aeruginosa 1000 mg/mL; Staphylococcus aureus 250 mg/mL.

Solubility: very soluble in water.

Methanol Very slightly soluble

Safety:

(15)

Mineral oil Practically insoluble

Propan-2-ol Practically insoluble

Propylene glycol(a) 1 in 0.8

Sesame oil Very slightly soluble

Water 1 in 0.5

(a) Slow to dissolve and requires heating and stirring.

Method of Manufacture

Imidurea is commercially prepared by a complex synthetic route.

Safety

Imidurea is widely used in cosmetics and topical pharmaceu- tical formulations and is generally regarded as a nontoxic and nonirritant material.(5) However, there have been some reports of contact dermatitis associated with imidurea, although these are relatively few considering its widespread use in cos- metics.(7–10)

Although imidurea releases formaldehyde, it does not appear to be associated with cross-sensitization with formalde- hyde or other formaldehyde-releasing compounds.

LD50 (mouse, oral): 7.2 g/kg(11,12) LD50 (rabbit, skin): > 8 g/kg

LD50 (rat, oral): 11.3 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Imidurea may be irritant to the eyes. Eye protection and gloves are recommended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (topical preparations). Accepted for use in cosmetics in Europe and the USA. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Diazolidinyl urea.

Diazolidinyl urea

Empirical formula: C8H14N4O7

Molecular weight: 278.23

CAS number: [78491-02-8]

Synonyms: Germall II; N-(hydroxymethyl)-N-(1,3-dihydroxy- methyl-2,5-dioxo-4-imidazolidinyl)-N'-(hydroxymethyl) urea.

LD50 (mouse, oral): 3.7 g/kg LD50 (rat, oral): 2.6 g/kg

Comments: the EINECS number for diazolidinyl urea is 278- 928-2.

Comments

Imidurea is the best known of a family of heterocyclic urea derivatives that are effective antimicrobial preservatives. Diazolidinyl urea has the greatest antimicrobial activity.

The EINECS number for imidurea is 254-372-6.

Specific References

Jacobs G, Henry SM, Cotty VF. The influence of pH, emulsifier, and accelerated ageing upon preservative requirements of o/w emulsions. J Soc Cosmet Chem 1975; 26: 105–117.

Rosen WE, Berke PA, Matzin T, Peterson AF. Preservation of cosmetic lotions with imidazolidinyl urea plus parabens. J Soc Cosmet Chem 1977; 28: 83–87.

Berke PA, Rosen WE. Imidazolidinyl urea activity against pseudomonas. J Soc Cosmet Chem 1978; 29: 757–766.

Wallha¨ usser KH. Imidazolidinyl urea. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 655–657.

Rosen WE, Berke PA. Germall 115: a safe and effective modern preservative. Cosmet Toilet 1977; 92(3): 88–89.

Rosen WE, Berke PA. Germall 115 and nonionic emulsifiers.

Cosmet Toilet 1979; 94(12): 47–48.

Fisher AA. Cosmetic dermatitis: part II. Reactions to some commonly used preservatives. Cutis 1980; 26: 136, 137, 141,

142, 147–148.

Dooms-Goossens A, De Boulle K, Dooms M, Degreef H. Imidazolidinyl urea dermatitis. Contact Dermatitis 1986; 14(5): 322–324.

O’Brien TJ. Imidazolidinyl urea (Germall 115) causing cosmetic dermatitis. Aust J Dermatol 1987; 28(1): 36–37.

Ziegler V, Ziegler B, Kipping D. Dose-response sensitization experiments with imidazolidinyl urea. Contact Dermatitis 1988; 19(3): 236–237.

Elder RL. Final report of the safety assessment for imidazolidinyl urea. J Environ Pathol Toxicol 1980; 4(4): 133–146.

Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. Cincinnati: US Department of Health, 1987: 5023.

Berke PA, Rosen WE. Germall II: a new broad-spectrum cosmetic preservative. Cosmet Toilet 1982; 97(6): 49–53.

Wallha¨ usser KH. Germall II. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 657–659.

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

11th edn. New York: Wiley, 2004: 2072.

General References

Berke PA, Rosen WE. Germall, a new family of antimicrobial preservatives for cosmetics. Am Perfum Cosmet 1970; 85(3): 55–

59.

Imidurea 361

Croshaw B. Preservatives for cosmetics and toiletries. J Soc Cosmet Chem 1977; 28: 3–16.

Decker RL, Wenninger JA. Frequency of preservative use in cosmetic formulas as disclosed to FDA-1987. Cosmet Toilet 1987; 102(12): 21–24.

Rosen WE, Berke PA. Germall 115: a safe and effective preservative. In: Kabara JJ, ed. Cosmetic and Drug Preservation Principles and Practice. New York: Marcel Dekker, 1984: 191–205.

BP: Inulin USPNF: Inulin

Synonyms

Beneo; Frutafit; oligofructose; polyfructose; Raftiline.

Chemical Name and CAS Registry Number

Inulin [9005-80-5]

Empirical Formula and Molecular Weight

C6H11O4(C6H11O4)nOH ≈5000

Structural Formula

Inulin is a naturally occurring polysaccharide consisting of a linear chain of linked D-fructose molecules, having one terminal glucose molecule.

Functional Category

Diagnostic aid; sweetening agent; tablet binder.

Applications in Pharmaceutical Formulation or Technology

Inulin has many potential uses in pharmaceutical applications, as a filler–binder in tablet formulations;(1) to stabilize therapeutic proteins;(2) or to enhance the dissolution of lipophilic drugs.(3) Methacrylated inulin hydrogels have been investigated for the development of colon-specific drug delivery systems.(4)

Inulin is used as a diagnostic agent to measure the glomerular filtration rate.(5) It is used in the food industry as a sweetener and stabilizer; and also as a pro-biotic, where it has been shown to provide protection against inflammatory and

malignant colonic diseases in animals.(6,7) It is also used as a noncaloric dietary fiber supplement.

Description

Inulin occurs as an odorless white powder with a neutral to slightly sweet taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for inulin.

Test BP 2004 USPNF 23

Identification + +

Acidity + 4.5–7.0

Clarity and color of solution + +

Microbial limit — 41000/g

Loss on drying 410.0% 410.0%

Specific rotation –36.58 to –40.58 –32.08 to –40.08

Residue on ignition 40.1% 40.05%

Sulfate 4200 ppm 40.05%

Calcium 4270 ppm 40.5%

Chloride 4170 ppm 40.014%

Heavy metals — 45 ppm

Arsenic 41 ppm —

Lead 42 ppm —

Oxalate + —

Glucose and fructose + +

Assay (dried basis) — 94.0–102.0%

Typical Properties

Acidity/alkalinity: pH = 4.5–7.0 (10% w/v aqueous solution)

Density: 1.35 g/cm3

Hygroscopicity: hygroscopic in moist air.

Melting point: 1788C

Solubility: soluble in hot water and solutions of dilute acids and alkalis; slightly soluble in cold water and organic solvents.

Specific gravity: 1.35

Stability and Storage Conditions

Inulin is slightly hygroscopic and should be stored at cool to normal temperatures, in air-tight and water-tight containers.

Incompatibilities

Inulin is incompatible with strong oxidizing agents.

Method of Manufacture

Inulin is extracted from the tubers of Dahlia variabilis, Helianthus, in a procedure similar to the extraction of sugar from sugar beet.

Inulin 363

Safety

Inulin is a naturally occurring plant polysaccharide and is one of the major constituents of the Compositae family. Inulin is recommended to diabetics, as it has a mild sweet taste, but is not absorbed and does not affect blood sugar levels. It is used widely in the food industry as a sweetener and stabilizer.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Inulin may cause mild irritation to the skin and the eyes. Eye protection and gloves are recommended.

Hollow spheres of inulin have been found to have both brittle and ductile properties. On compression, these spheres will undergo fragmentation followed by plastic deformation, resulting in better compressibility over solid inulin spheres. In its amorphous state, inulin has a high glass transition temperature, slow crystallization, and low hygroscopicity. As a binder in solid dosage forms, inulin can increase the dissolution rate of drugs such as diazepam and can enhance the stability of other lipophilic drug molecules.(3,8) Experimen- tally, methacrylated inulin hydrogels have been synthesized specifically for colon targeting.(9,10)

Inulin is used as a diagnostic agent to measure the glomerular filtration rate. It has also entered the food supplement market as a prebiotic and as a noncaloric dietary fiber supplement. Radio-labelled forms of inulin are available as radiochemicals for research.

Specific References

Eissens AC, Bolhuis GK, Hinrichs WL, Frijlink HW. Inulin as filler- binder for tablets prepared by direct compaction. Eur J Pharm Sci 2002; 15(1): 31–38.

Eriksson HJ, Hinrichs WL, Van Veen B, et al. Investigations into the stabilization of drugs by sugar glasses: I. Tablets prepared from stabilized alkaline phosphate. Int J Pharm 2002; 249(1–2): 59–70.

International Pharmaceutical Excipients Council Europe. IPEC Europe News Jan 2003.

Van den Mooter G, Vervoort L, Kinget R. Characterization of methacrylated inulin hydrogels designed for colon targeting: in vitro release of BSA. Pharm Res 2003; 20(2): 303–307.

Windfeld S, Jonassen TE, Christensen S. [3H]Inulin as a marker for glomerular filtration rate. Am J Physiol Renal Physiol 2003; 285(3): 575–576.

Reddy BS, Hamid R, Rao CV. Effect of dietary oligofructose and inulin on colonic preneoplastic abberant crypt foci inhibition. Carcinogenesis 1997; 18(7): 1371–1374.

Delzenne N, Cherbut C, Neyrinck A. Prebiotics: actual and potential effects in inflammatory and malignant colonic diseases. Curr Opin Clin Nutr Metab Care 2003; 6(5): 581–586.

Bolhuis GK, Eissens AC, Adrichem TP, et al. Hollow filler-binders as excipients for direct compaction. Pharm Res 2003; 20(3): 515– 518.

Maris B, Verheyden L, Van Reeth K, et al. Synthesis and characterization of inulin-azo hydrogels designed for colon targeting. Int J Pharm 2001; 213: 143–152.

Vervoort L, Van der Mooter G, Ausutijns P, et al. Inulin hydrogels as carriers for colonic drug targetting: I. Synthesis and character- ization of methacrylated inulin and hydrogel formation. Pharm Res 1997; 14(12): 1730–1737.

Iron oxide black: Bayferrox 306; black magnetic oxide; black oxide, precipitated; black rouge; CI 77499; E172; ethiops iron; ferric ferrous oxide; ferrosoferric oxide; iron oxide; iron (II, III) oxide; iron (III) oxide; iron (II) oxide, black; iron oxides (Fe3O4); magnetite; pigment black 11; triiron tetraoxide.

Iron (III) oxide hydrated: Bayferrox 920Z; CI 77492; E172;

Description

Iron oxides occur as yellow, red, black, or brown powder. The color depends on the particle size and shape, and the amount of combined water.

Pharmacopeial Specifications

—

Typical Properties

Density: 5.1 g/cm3 for iron oxide black (Fe O )

ferric hydroxide; ferric hydroxide oxide; ferric hydrate; ferric 3 4

oxide hydrated; iron hydrate; iron hydroxide; iron hydroxide oxide; yellow ochre; yellow iron oxide.

Iron oxide red: anhydrous ferric oxide; anhydrous iron (III) oxide; Bayferrox 105M; CI 77499; diiron trioxide; E172; mapico red; red ferric oxide.

Iron oxide yellow monohydrate: E172; hydrated ferric oxide; iron (III) oxide monohydrate, yellow; mapico yellow; pigment yellow 42; yellow ferric oxide.

Chemical Name and CAS Registry Number

Iron oxides [977053-38-5]

Iron oxide black [1317-61-9]

Iron (III) oxide hydrated [20344-49-4]

Iron oxide red [1309-37-1]

Iron oxide yellow monohydrate [51274-00-1]

Empirical Formula and Molecular Weight

Iron oxides are defined as inorganic compounds consisting of any one of or combinations of synthetically prepared iron oxides, including the hydrated forms.

Functional Category

Colorants.

Applications in Pharmaceutical Formulation or Technology

Iron oxides are widely used in cosmetics, foods, and pharmaceutical applications as colorants and UV absor- bers.(1–3) As inorganic colorants they are becoming of increas- ing importance as a result of the limitations affecting some synthetic organic dyestuffs. However, iron oxides also have restrictions in some countries on the quantities that may be consumed and technically their use is restricted because of their limited color range and their abrasiveness.

Melting point: 15388C for iron oxide black (Fe3O4)

Solubility: soluble in strong mineral acids; practically insoluble in water (for iron oxide black, Fe3O4).

Stability and Storage Conditions

Iron oxides should be stored in well-closed containers stored in a cool, dry, place.

Incompatibilities

Iron oxides have been reported to make hard gelatin capsules brittle at higher temperatures when the residual moisture is 11–12%. This factor affects the use of iron oxides for coloring hard gelatin capsules, and will limit the amount that can be incorporated into the gelatin material.

Method of Manufacture

Fe2+ salt solutions are precipitated and oxidized to black or brown iron oxide.

Safety

Iron oxides are widely used in cosmetics, foods, and oral and topical pharmaceutical applications. They are generally regarded as nontoxic and nonirritant excipients. The use of iron oxide colorants is limited in some countries, such as the USA, to a maximum ingestion of 5 mg of elemental iron per day.

For iron oxide red (Fe2O3):

LD50 (mouse, IP): 5.4 g/kg(4) LD50 (rat, IP): 5.5 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled. In the UK, the occupational exposure limits for iron oxide fumes (as Fe) are 5 mg/m3 long-term (8-hour TWA) and 10 mg/m3 short-term.(5)

Regulatory Status

Accepted for use as a food additive in Europe. Included in nonparenteral medicines licensed in many countries including Japan, UK, and USA.

Iron Oxides 365

Table I: Joint FAO/WHO Expert Committee on Food Additive specifications for iron oxides.

Test FAO/WHO

Table II: Specifications for iron oxide black, iron oxide red, and iron oxide yellow monohydrate from JPE 2004.

The EINECS number for iron oxide red (Fe O ) is 215-168-2.

(dried basis)

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

Joint FAO/WHO Expert committee on Food Additives (1992). Iron oxides. http://apps3.fao.org/jecfa/additive_specs/docs/0/addi- tive-0230.htm (accessed 12 May 2005).

2 3 7 Japan Pharmaceutical Excipients Council. Japanese Pharmaceu-

The EINECS number for iron oxide black (Fe3O4) is 215-277- 5.

Although iron oxides are not included in any pharmaco- peias, the Joint FAO/WHO Expert Committee on Food Additives has issued specifications for iron oxides, see Table I.(6) Specifications for iron oxide black,(7) iron oxide red,(8) and iron oxide yellow monohydrate(9) are included in the Japanese Pharmaceutical Excipients (JPE) 2004; see Table II.

Specific References

Rowe RC. Opacity of tablet film coatings. J Pharm Pharmacol

1984; 36: 569–572.

Rowe RC. Synthetic iron oxides: ideal for pharmaceutical color- ants. Pharm Int 1984; 5: 221–224.

Ceschel GC, Gibellini M. Use of iron oxides in the film coating of tablets. Farmaco Ed Prat 1980; 35: 553–563.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2111–2112.

tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 102–103.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 746–747.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 939.

BP: Isomalt PhEur: Isomaltum

Synonyms

GalenIQ; hydrogenated isomaltulose; hydrogenated palati- nose; E953; Isomaltidex 16500; Palatinit.

Chemical Name and CAS Registry Number

Isomalt [64519-82-0]

Isomalt is a mixture of two stereoisomers:

6-O-a-D-glucopyranosyl-D-sorbitol (1,6-GPS) [534-73-6] 1-O-a-D-glucopyranosyl-D-mannitol dihydrate (1,1-GPM) [20942-99-8]

Empirical Formula and Molecular Weight

C12H24O11 344.32 (for anhydrous) C12H24O11·2H2O 380.32 (for dihydrate)

Structural Formula

Generally, isomalt comprises a mixture of 1,6-GPS and 1,1- GPM. 1,6-GPS crystallizes without water and is more soluble

than 1,1-GPM. By shifting the ratio of the two components, the solubility and crystal water content can be adjusted, see Section

10. GalenIQ 720 has a GPM : GPS ratio of 1 : 1; GalenIQ 721

has a GPM : GPS ratio of 1 : 3.

Functional Category

Base for medicated confectionery; coating agent; granulating agent; sweetening agent; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Isomalt is a noncariogenic excipient used in a variety of pharmaceutical preparations including tablets or capsules, coatings, sachets, and suspensions, and in effervescent tablets. It can also be used in direct compression and wet granulation.(1) In buccal applications such as chewable tablets it is commonly used because of its negligible negative heat of solution, mild sweetness, and ‘mouth feel’.(2,3) It is also used widely in lozenges, sugar-free chewing gum, and hard-boiled candies, and as a sweetening agent in confectionery for diabetics.

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