kywods

Osmolarity: the osmolarity of an aqueous maltitol solution is similar to that of a sucrose solution of the same concentra- tion. A 10% v/v aqueous solution of Lycasin 80/55 (Roquette) is iso-osmotic with serum.

Refractive index: n20 = 1.478

Solubility: miscible with ethanol (provided the ethanol con- centration is less than 55%), glycerin, propylene glycol, and water. Insoluble in mineral and vegetable oils.

Viscosity (dynamic): maltitol solution is a viscous, syrupy, liquid. At 208C, a solution of Lycasin 80/55 (Roquette) containing 75% of dry substances has a viscosity of approximately 2000 mPa s (2000 cP). With increasing tem- perature, the viscosity of a maltitol solution is reduced; see Figure 1. The viscosity of maltitol solutions also decreases with decreasing concentration of dry solids, at a constant temperature. Maltitol solution may also be mixed with sorbitol solution to obtain blends of a desired viscosity.

Stability and Storage Conditions

Maltitol solution is stable for at least 2 years at room temperature and pH 3–9. Following storage for 3 months at 508C, maltitol solution at pH 2 underwent slight hydrolysis (1.2%) and became yellow colored. At pH 3, and the same storage conditions, no color change was apparent although very slight hydrolysis occurred (0.2%). At pH 4–9, no hydrolysis occurred although a very slight yellow color was formed under alkaline conditions.(2)

Maltitol Solution 441

Handling Precautions

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

Regulatory Status

Accepted for use in confectionery, foods, and nonparenteral pharmaceutical formulations in Europe and the USA. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Maltitol; sorbitol.

Figure 1: Viscosity of maltitol solution (Lycasin 80/55), containing 75% of dry substances, at different temperatures.

Formulations containing maltitol solution should be pre- served with an antimicrobial preservative such as sodium benzoate or a mixture of parabens. Maltitol solution is noncrystallizing.

Maltitol solution should be stored in a well-closed container, in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Maltitol solution is prepared by the hydrogenation of a high- maltose syrup that is obtained from starch by enzymatic hydrolysis. The maltitol solution produced from this process consists of the hydrogenated homologs of the oligosaccharides contained in the original syrup.

Safety

Maltitol solution is used in oral pharmaceutical formulations, confectionery, and food products and is considered to be less cariogenic than sucrose.(3–6) It is generally regarded as a nontoxic, nonallergenic, and nonirritant material. However, excessive oral consumption (more than 50 g daily) may cause flatulence and diarrhea.

The WHO, in considering the safety of maltitol solution, did not set a value for the acceptable daily intake since the levels used in food to achieve a desired effect were not considered a hazard to health.(7,8)

LD50 (rat, IP): 20 g/kg(9)

Comments

Hydrogenated glucose syrup is a generic term used to describe aqueous mixtures containing mainly D-maltitol, along with D- sorbitol and hydrogenated oligosaccharides and polysacchar- ides. Such mixtures can vary widely in their composition and hence physical and chemical properties. Products containing up to 90% of maltitol are usually known as maltitol syrup or maltitol solution. Preparations containing a minimum of 98% of maltitol are designated maltitol.

Specific References

Grenby TH. Dental properties of antiseptic throat lozenges formulated with sugars or Lycasin. J Clin Pharm Ther 1995; 20: 235–241.

Roquette. Technical literature: Lycasin the sweetener for sugarless pharmaceuticals. 1993.

Frostell G, Birkhed D. Acid production from Swedish Lycasin (candy quality) and French Lycasin (80/55) in human dental plaques. Caries Res 1978; 12: 256–263.

Grenby TH. Dental and nutritional effects of Lycasins replacing sucrose in the diet of laboratory rats. J Dent Res 1982; 61: 557.

Wu¨ rsch P, Koellreutter B. Maltitol and maltotriitol as inhibitors of acid production in human dental plaque. Caries Res 1982; 16: 90–

95.

Havenaar R, Drost JS, de Stoppelaar JD, et al. Potential cariogenicity of Lycasin 80/55 in comparison to starch, sucrose, xylitol, sorbitol and L-sorbose in rats. Caries Res 1984; 18: 375– 384.

FAO/WHO. Evaluation of certain food additives and contami- nants: Thirty-third report of the joint FAO/WHO expert commit- tee on food additives. World Health Organ Tech Rep Ser 1989; No. 776.

FAO/WHO. Evaluation of certain food additives and contami- nants: Forty-sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1997; No. 868.

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

General References

Le Bot Y. Lycasin for confections. Manuf Confect 1983; (Dec): 69–74.

BP: Maltodextrin PhEur: Maltodextrinum USPNF: Maltodextrin

Synonyms

C*Dry MD; C*PharmDry; Glucidex; Glucodry; Lycatab DSH; Maldex; Malta*Gran; Maltrin; Maltrin QD; Paselli MD10 PH; Rice*Trin; Star-Dri; Tapi.

Chemical Name and CAS Registry Number

Maltodextrin [9050-36-6]

Empirical Formula and Molecular Weight

(C6H10O5)n·H2O 900–9000

The USPNF 23 describes maltodextrin as a nonsweet, nutritive saccharide mixture of polymers that consist of D-glucose units, with a dextrose equivalent (DE) less than 20; see also Section 18. The D-glucose units are linked primarily by a-(1→4) bonds but there are branched segments linked by a-(1→6) bonds. It is prepared by the partial hydrolysis of a food-grade starch with suitable acids and/or enzymes.

Structural Formula

Functional Category

Coating agent; tablet and capsule diluent; tablet binder; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Maltodextrin is used in tablet formulations as a binder and diluent in both direct-compression and wet-granulation or

agglomeration processes.(1–7) Maltodextrin appears to have no adverse effect on the rate of dissolution of tablet and capsule formulations; magnesium stearate 0.5–1.0% may be used as a lubricant. It has been used as a carrier in a spray-dried redispersible oil-in-water emulsion to improve the bioavail- ability of poorly soluble drugs.(8) Maltodextrin may also be used as a tablet film former in aqueous film-coating processes. Maltodextrin grades with a high DE value are particularly useful in chewable tablet formulations.

Maltodextrin may also be used in pharmaceutical formula- tions to increase the viscosity of solutions and to prevent the crystallization of syrups. Therapeutically, maltodextrin is often used as a carbohydrate source in oral nutritional supplements because solutions with a lower osmolarity than isocaloric dextrose solutions can be prepared. At body osmolarity, maltodextrin solutions provide a higher caloric density than sugars.

Maltodextrin is also widely used in confectionery and food products, as well as personal care applications. See Table I.

Table I: Uses of maltodextrin.

Use Concentration (%)

Aqueous film-coating 2–10

Carrier 10–99

Crystallization inhibitor for lozenges and syrups 5–20

Osmolarity regulator for solutions 10–50

Spray-drying aid 20–80

Tablet binder (direct compression) 2–40

Tablet binder (wet granulation) 3–10

Description

Maltodextrin occurs as a nonsweet, odorless, white powder or granules. The solubility, hygroscopicity, sweetness, and com- pressibility of maltodextrin increase as the DE increases. The USPNF 23 states that it may be physically modified to improve its physical and functional characteristics.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for maltodextrin.

Test PhEur 2005 USPNF 23

Identification + —

Characters + —

Microbial limits + +

pH (20% w/v solution) 4.0–7.0 4.0–7.0

Loss on drying 46.0% 46.0%

Residue on ignition 40.5% 40.5%

Heavy metals 410 ppm 45 ppm

Protein — 40.1%

Sulfur dioxide 420 ppm 440 ppm

Dextrose equivalent + 420

Maltodextrin 443

SEM: 1

Excipient: Maltodextrin (Maltrin M100) Manufacturer: Grain Processing Corp. Magnification: 100×

SEM: 2

Excipient: Maltodextrin (Maltrin QD M500)

Manufacturer: Grain Processing Corp.

Magnification: 100×

Typical Properties

Angle of repose:

35.28 for Maltrin QD M500;(5)

28.48 for Maltrin M510.(5)

Density (bulk):

0.43 g/cm3 for Lycatab DSH;

0.26 g/cm3 for Maltrin QD M500;

0.51 g/cm3 for Maltrin M040;

0.54 g/cm3 for Maltrin M050;

0.54 g/cm3 for Maltrin M100;

0.57 g/cm3 for Maltrin M150;

0.61 g/cm3 for Maltrin M180;

0.30 g/cm3 for Maltrin QD M440;

0.56 g/cm3 for Maltrin M510;

0.37 g/cm3 for Maltrin QD M550;

0.40 g/cm3 for Maltrin QD M580;

0.13 g/cm3 for Maltrin M700.

Density (tapped):

0.63 g/cm3 for Lycatab DSH;

0.32 g/cm3 for Maltrin QD M500;

0.54 g/cm3 for Maltrin M510.(5)

Density (true):

1.419 g/cm3;

1.334 g/cm3 for Maltodextrin FCC;

1.410 g/cm3 for Maltrin M500;

1.425 g/cm3 for Maltrin M510.

Moisture content: hygroscopicity increases as DE increases. Maltodextrin is slightly hygroscopic at relative humidities less than 50%. At relative humidities greater than 50%, the hygroscopicity of maltodextrin increases nonlinearly.

Particle size distribution: Maltrin is available in various grades with different particle size distributions.

For Lycatab DSH: maximum of 15% greater than 200 mm, and minimum of 80% greater than 50 mm in size.

Solubility: freely soluble in water; slightly soluble in ethanol (95%). Solubility increases as DE increases.

Specific surface area:

0.54 m2/g for Maltrin QD M500;

0.31 m2/g for Maltrin M510.(5)

Viscosity (dynamic): less than 20 mPa s (20 cP) for a 20% w/v aqueous solution of Lycatab DSH. The viscosity of maltodextrin solutions decreases as the DE increases.

Viscosity is 3.45 mPa s for a 20% w/v aqueous dispersion of Star-Dri (Tate & Lyle).

Stability and Storage Conditions

Maltodextrin is stable for at least 1 year when stored at a cool temperature (<308C) and less than 50% relative humidity. Maltodextrin solutions may require the addition of an antimicrobial preservative.

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

Incompatibilities

Under certain pH and temperature conditions maltodextrin may undergo Maillard reactions with amino acids to produce yellowing or browning. Incompatible with strong oxidizing agents.

Method of Manufacture

Maltodextrin is prepared by heating and treating starch with acid and/or enzymes in the presence of water. This process partially hydrolyzes the starch, to produce a solution of glucose polymers of varying chain length. This solution is then filtered, concentrated, and dried to obtain maltodextrin.

444 Maltodextrin

Safety

Maltodextrin is a readily digestible carbohydrate with a nutritional value of approximately 17 kJ/g (4 kcal/g). In the USA, it is generally recognized as safe (GRAS) as a direct human food ingredient at levels consistent with current good manufacturing practices. As an excipient, maltodextrin is generally regarded as a nonirritant and nontoxic material.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection is recom- mended. Maltodextrin should be handled in a well-ventilated environment and excessive dust generation should be avoided.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral tablets and granules). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Corn syrup solids; dextrates; dextrin; starch.

Corn syrup solids

Comments: corn syrup solids are glucose polymers with a DE 5 20 and are prepared, in a similar manner to maltodextrin, by the partial hydrolysis of starch.

Comments

Various different grades of maltodextrin are commercially available for food and pharmaceutical applications from a number of suppliers: e.g. Lycatab DS (Roquette Fre`res), Maltrin (Grain Processing Corp.) and Star-Dri (Tate & Lyle). The grades have different physical properties such as solubility and viscosity, depending upon their DE value. The dextrose equivalent (DE) value is a measure of the extent of starch- polymer hydrolysis and is defined as the reducing power of a substance expressed in grams of D-glucose per 100 g of the dry substance.

A specification for maltodextrin is contained in the Food Chemicals Codex (FCC). The EINECS number for maltodex- trin is 232-940-4.

Specific References

Li LC, Peck GE. The effect of moisture content on the compression properties of maltodextrins. J Pharm Pharmacol 1990; 42(4): 272–

275.

Li LC, Peck GE. The effect of agglomeration methods on the micrometric properties of a maltodextrin product Maltrin 150. Drug Dev Ind Pharm 1990; 16: 1491–1503.

Papadimitriou E, Efentakis M, Choulis NH. Evaluation of maltodextrins as excipients for direct compression tablets and their influence on the rate of dissolution. Int J Pharm 1992; 86: 131–136.

Visavarungroj N, Remon JP. Evaluation of maltodextrin as binding agent. Drug Dev Ind Pharm 1992; 18: 1691–1700.

Mollan MJ, C¸ elik M. Characterization of directly compressible maltodextrins manufactured by three different processes. Drug Dev Ind Pharm 1993; 19: 2335–2358.

Mun˜ oz-Ruiz A, Monedero Perales MC, Velasco Antequera MV, Jime´nez-Castellanos MR. Physical and rheological properties of raw materials. STP Pharma (Sci) 1993; 3: 307–312.

Symecko CW, Romero AJ, Rhodes CT. Comparative evaluation of two pharmaceutical binders in the wet granulation of hydrochlor- othiazide: Lycatb DSH vs. Kollidon 30. Drug Dev Ind Pharm 1993; 19: 1131–1141.

Dollo G, Le Carre P, Guerin A, et al. Spray-dried redispersible oil- in-water emulsion to improve oral bioavailability of poorly soluble drugs. Eur J Pharm Sci 2003; 19(4): 273–280.

General References

Grain Processing Corporation. Technical literature: Maltrin maltodex- trins and corn syrup solids for pharmaceuticals, 1998.

Primera Foods. Maltodextrins. http://www.primerafoods.com/mss.asp (accessed 24 August 2005).

Roquette Fre`res. Technical literature: Lycatab DSH excipient for wet granulation, 1992.

Shah A, Buckton G, Booth S. Characterisation of maltodextrins using isothermal microcalorimetry. J Pharm Pharmacol 2000; 52 (Suppl.):

Hydroxy-2-methyl-(1,4-pyran); 3-hydroxy-2-methyl-4-pyr- one; larixinic acid; 2-methyl-3-hydroxy-4-pyrone; 2-methyl pyromeconic acid; Palatone; Veltol.

Chemical Name and CAS Registry Number

3-Hydroxy-2-methyl-4H-pyran-4-one [118-71-8]

Empirical Formula and Molecular Weight

C6H6O3 126.11

Structural Formula

Functional Category

Flavor enhancer; flavoring agent.

Applications in Pharmaceutical Formulation or Technology

Maltol is used in pharmaceutical formulations and food products as a flavoring agent or flavor enhancer. In foods, it is used at concentrations up to 30 ppm, particularly with fruit flavorings, although it is also used to impart a freshly baked odor and flavor to bread and cakes. When used at concentra- tions of 5–75 ppm, maltol potentiates the sweetness of a food product, permitting a reduction in sugar content of up to 15% while maintaining the same level of sweetness. Maltol is also used at low levels in perfumery.

Description

White crystalline solid with a characteristic, caramel-like odor and taste. In dilute solution it possesses a sweet, strawberry-like or pineapple-like flavor and odor.

Pharmacopeial Specifications

See Section 18.

Typical Properties

Acidity/alkalinity: pH = 5.3 (0.5% w/v aqueous solution) Melting point: 162–1648C (begins to sublime at 938C) Solubility: see Table I.

Table I: Solubility of maltol.

Solvent Solubility at 208C

Chloroform Freely soluble

Diethyl ether Sparingly soluble

Ethanol (95%) 1 in 21

Glycerin 1 in 80

Propan-2-ol 1 in 53

Propylene glycol 1 in 28

Water 1 in 83

Stability and Storage Conditions

Maltol solutions may be stored in glass or plastic containers. The bulk material should be stored in a well-closed container, protected from light, in a cool, dry place. See also Section 12.

Incompatibilities

Concentrated solutions in metal containers, including some grades of stainless steel, may discolor on storage.

Method of Manufacture

Maltol is mainly isolated from naturally occurring sources such as beechwood and other wood tars; pine needles; chicory; and the bark of young larch trees. It may also be synthesized by the alkaline hydrolysis of streptomycin salts or by a number of other synthetic methods.

Safety

Maltol is generally regarded as an essentially nontoxic and nonirritant material. In animal feeding studies, it has been shown to be well tolerated with no adverse toxic, reproductive, or embryogenic effects observed in rats and dogs fed daily intakes of up to 200 mg/kg of maltol, for 2 years.(1) The WHO has set an acceptable daily intake for maltol at up to 1 mg/kg body-weight.(2) A case of allergic contact dermatitis, attributed to the use of maltol in a lip ointment, has been reported.(3)

LD50 (chicken, oral): 3.72 g/kg(4) LD50 (guinea pig, oral): 1.41 g/kg LD50 (mouse, oral): 0.85 g/kg LD50 (mouse, SC): 0.82 g/kg

LD50 (rabbit, oral): 1.62 g/kg LD50 (rat, oral): 1.41 g/kg

446 Maltol

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Maltol should be used in a well-ventilated environment. Eye protection is recommended.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral solutions and syrups). Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Ethyl maltol.

Comments

Maltol is a good chelating agent and various metal com- plexes, e.g., aluminum maltol and ferric maltol have been investigated as potentially useful therapeutic or experimental agents.(5–8)

Maltol is a constituent of Korean red ginseng.(9)

Although not included in any pharmacopeias, a specifica- tion for maltol is contained in the Food Chemicals Codex (FCC), see Table II.(10)

Table II: Food Chemicals Codex specifications for maltol.

Test FCC 1996

Identification +

Heavy metals (as lead) 40.002%

Lead 410 ppm

Melting range 160–1648C

Residue on ignition 40.2%

Water 40.5%

Assay 599.0%

Specific References

Gralla EJ, Stebbins RB, Coleman GL, Delahunt CS. Toxicity studies with ethyl maltol. Toxicol Appl Pharmacol 1969; 15: 604–

613.

FAO/WHO. Evaluation of certain food additives. Twenty-fifth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1981; No. 669.

Taylor AE, Lever L, Lawrence CM. Allergic contact dermatitis from strawberry lipsalve. Contact Dermatitis 1996; 34(2): 142–

143.

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

11th edn. New York: Wiley, 2004: 2275.

Finnegan MM, Rettig SJ, Orvig C. A neutral water-soluble aluminum complex of neurological interest. J Am Chem Soc 1986; 108: 5033–5035.

Barrand MA, Callingham BA, Hider RC. Effects of the pyrones, maltol and ethyl maltol, on iron absorption from the rat small intestine. J Pharm Pharmacol 1987; 39: 203–211.

Singh RK, Barrand MA. Lipid peroxidation effects of a novel iron compound, ferric maltol. A comparison with ferrous sulfate. J Pharm Pharmacol 1990; 42: 276–279.

Kelsey SM, Hider RC, Bloor JR, et al. Absorption of low and therapeutic doses of ferric maltol, a novel ferric iron compound, in iron deficient subjects using a single dose iron absorption test. J Clin Pharm Ther 1991; 16: 117–122.

Wei J. Studies on the constituents of Korean red ginseng – the isolation and identification of 3-hydroxy-2-methyl-4-pyrone [in Chinese]. Acta Pharmaceutica Sinica 1982; 17: 549–550.

Food Chemicals Codex, 4th edn. Washington, DC: National Academy Press, 1996: 240–241.

JP: Maltose USPNF: Maltose

Synonyms

Advantose 100; Finetose; Finetose F; 4-O-a-D-glucopyranosyl- b-D-glucose; 4-(a-D-glucosido)-D-glucose; malt sugar; malto- biose; Maltodiose; Maltose HH; Maltose HHH; Sunmalt; Sunmalt S.

Chemical Name and CAS Registry Number

4-O-a-D-Glucopyranosyl-b-D-glucopyranose anhydrous [69-

79-4]

4-O-a-D-Glucopyranosyl-b-D-glucopyranose monohydrate [6363-53-7]

Empirical Formula and Molecular Weight

C12H22O11 342.31 (anhydrous)

C12H22O11·H2O 360.31 (monohydrate)

Structural Formula

Functional Category

Sweetening agent; tablet diluent.

Applications in Pharmaceutical Formulation or Technology

Maltose is a disaccharide carbohydrate widely used in foods and pharmaceuticals. In parenteral products, maltose may be used as a source of sugar, particularly for diabetic patients.

Crystalline maltose is used as a direct-compression tablet excipient in chewable and nonchewable tablets.(1–3)

Description

Maltose occurs as white crystals or as a crystalline powder. It is odorless and has a sweet taste approximately 30% that of sucrose.

SEM: 1

Excipient: Crystalline maltose Manufacturer: SPI Pharma Group Lot No.: 8K110947

Magnification: 100×

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for maltose.

Test JP 2001 USPNF 23

Identification + +

Specific rotation +1268 to +1318 —

pH 4.5–6.5 —

for anhydrous — 3.7–4.4

for monohydrate — 4.0–5.5

Clarity and color of solution + —

Chloride <0.018% —

Sulfate <0.024% —

Heavy metals <4 ppm 45 ppm

Arsenic <1.3 ppm —

Dextrin, soluble starch and sulfite + +

Nitrogen <0.01% —

Related substances + —

Loss on drying <0.5% —

for monohydrate — 5.0–6.5%

Residue on ignition <0.10% 40.05%

Assay (dried basis) >98.0% >92.0%

Typical Properties

Acidity/alkalinity: pH = 4.5–6.5 for a 10% w/v aqueous solution.

448 Maltose

Angle of repose: 37.18 for Advantose 100.(3)

Density (bulk): 0.67–0.72 g/cm3 for Advantose 100.(1) Density (tapped): 0.73–0.81 g/cm3 for Advantose 100.(1) Dissociation constant: pKa = 12.05 at 218C

Flash point: >1498C for Advantose 100.(1)

Flowability: 18% (Carr compressibility index) for Advantose

100.(3)

Melting point: 120–1258C.(4)

Particle size distribution: 15–20% greater than 300 mm, and 70–75% greater than 150 mm in size for Advantose 100.(1)

Specific surface area: 0.08 m2/g for Advantose 100.(1)

Solubility: very soluble in water; very slightly soluble in cold ethanol (95%); practically insoluble in ether.

Stability and Storage Conditions

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

Incompatibilities

Maltose may react with oxidizing agents.

Method of Manufacture

Maltose monohydrate is prepared by the enzymatic degrada- tion of starch.

Safety

Maltose is used in oral and parenteral pharmaceutical formulations and is generally regarded as an essentially nontoxic and nonirritant material. However, there has been a single report of a liver transplantation patient with renal failure who developed hyponatremia following intravenous infusion of normal immunoglobulin in 10% maltose. The effect, which recurred on each of four successive infusions, resembled that of hyperglycemia and was thought to be due to accumulation of maltose and other osmotically active metabolites in the extracellular fluid.(4)

LD50 (mouse, IV): 26.8 g/kg(5) LD50 (mouse, SC): 38.6 g/kg LD50 (rabbit, IV): 25.2 g/kg LD50 (rat, IP): 30.6 g/kg

LD50 (rat, IV): 15.3 g/kg LD50 (rat, oral): 34.8 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, rubber or

plastic gloves, and a dust respirator are recommended. When heated to decomposition, maltose emits acrid smoke and irritating fumes.

Regulatory Status

In the USA, maltose is considered as a food by the FDA and is therefore not subject to food additive and GRAS regulations. Included in the FDA Inactive Ingredients Guide (oral solutions). Included in the Canadian List of Acceptable Non-medicinal Ingredients. Included in parenteral products available in a number of countries worldwide.

Related Substances

Glucose, liquid.

Comments

Crystalline maltose, e.g. Advantose 100 (SPI Pharma Group), is spray-dried to produce spherical particles with good flow properties. The material is also nonhygroscopic and is highly compressible.

The EINECS number for maltose is 200-716-5.

Specific References

SPI Pharma Group. Technical literature: Advantose 100 maltose, 2004.

Bowe KE, Billig JL, Schwartz JB, et al. Crystalline maltose: a direct compression pharmaceutical excipient. Pharm Technol Eur 1998; 10(5): 34, 36, 37, 40.

Mulderrig KB. Placebo evaluation of selected sugar-based exci- pients in pharmaceutical and nutraceutical tableting. Pharm Technol 2000; 24(5): 34, 36, 38, 40, 42, 44.

Palevsky PM, Rendulic D, Diven WF. Maltose-induced hypo- natremia. Ann Intern Med 1993; 118(7): 526–528.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2275.

General References

Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 299.

BP: Mannitol JP: D-Mannitol

PhEur: Mannitolum USP: Mannitol

Synonyms

Cordycepic acid; C*PharmMannidex; E421; manna sugar;

D-mannite; mannite; Mannogem; Pearlitol.

Chemical Name and CAS Registry Number

D-Mannitol [69-65-8]

Empirical Formula and Molecular Weight

C6H14O6 182.17

Structural Formula

Functional Category

Diluent; diluent for lyphilized preparations; sweetening agent; tablet and capsule diluent; tonicity agent.

Applications in Pharmaceutical Formulation or Technology

Mannitol is widely used in pharmaceutical formulations and food products. In pharmaceutical preparations it is primarily used as a diluent (10–90% w/w) in tablet formulations, where it is of particular value since it is not hygroscopic and may thus be used with moisture-sensitive active ingredients.(1,2)

Mannitol may be used in direct-compression tablet applica- tions,(3–7) for which the granular and spray-dried forms are available, or in wet granulations.(8) Granulations containing mannitol have the advantage of being dried easily. Specific tablet applications include antacid preparations, glyceryl trinitrate tablets, and vitamin preparations. Mannitol is commonly used as an excipient in the manufacture of chewable tablet formulations because of its negative heat of solution, sweetness, and ‘mouth feel’.(9,10)

In lyophilized preparations, mannitol (20–90% w/w) has been included as a carrier to produce a stiff, homogeneous cake that improves the appearance of the lyophilized plug in a vial.(11–20) A pyrogen-free form is available specifically for this use.

Mannitol has also been used to prevent thickening in aqueous antacid suspensions of aluminum hydroxide (<7% w/v). It has been suggested as a plasticizer in soft-gelatin capsules, as a component of sustained-release tablet formula- tions,(21) and as a carrier in dry powder inhalers.(22,23) It is also

used as a diluent in rapidly dispersing oral dosage forms.(24,25) It is used in food applications as a bulking agent.

Therapeutically, mannitol administered parenterally is used as an osmotic diuretic, as a diagnostic agent for kidney function, as an adjunct in the treatment of acute renal failure, and as an agent to reduce intracranial pressure, treat cerebral edema, and reduce intraocular pressure. Given orally, mannitol is not absorbed significantly from the GI tract, but in large doses it can cause osmotic diarrhea; see Section 14.

Description

Mannitol is D-mannitol. It is a hexahydric alcohol related to mannose and is isomeric with sorbitol.

Mannitol occurs as a white, odorless, crystalline powder, or free-flowing granules. It has a sweet taste, approximately as sweet as glucose and half as sweet as sucrose, and imparts a cooling sensation in the mouth. Microscopically, it appears as orthorhombic needles when crystallized from alcohol. Manni- tol shows polymorphism.(26)

Pharmacopeial Specifications

See Table I.

SEM: 1

Excipient: Mannitol Manufacturer: Merck Magnification: 50×

Voltage: 3.5 kV

450 Mannitol

SEM: 2

Excipient: Mannitol Manufacturer: Merck Magnification: 500×

Voltage: 3.5 kV

SEM: 3

Excipient: Mannitol powder Manufacturer: SPI Polyols Inc. Lot No: 3140G8

Magnification: 100×

Typical Properties

Compressibility: see Figure 1.

Density (bulk):

0.430 g/cm3 for powder;

0.7 g/cm3 for granules.

Density (tapped):

0.734 g/cm3 for powder;

0.8 g/cm3 for granules.

Density (true): 1.514 g/cm3

Dissociation constant: pKa = 13.5 at 188C

Flash point: <1508C

Flowability: powder is cohesive, granules are free flowing.

Heat of combustion: 16.57 kJ/g (3.96 kcal/g)

Heat of solution: —120.9 J/g (—28.9 cal/g) at 258C

Melting point: 166–1688C

SEM: 4

Excipient: Mannitol granular Manufacturer: SPI Polyols Inc. Lot No: 2034F8

Magnification: 100×

Moisture content: see Figure 2.

Osmolarity: a 5.07% w/v aqueous solution is isoosmotic with serum.

Particle size distribution:

Pearlitol 300 DC: maximum of 0.1% greater than 500 mm and minimum of 90% greater than 200 mm in size; Pearlitol 400 DC: maximum of 20% greater than 500 mm and minimum of 85% greater than 100 mm in size; Pearlitol 500 DC: maximum of 0.5% greater than 841 mm and minimum of 90% greater than 150 mm in size.

Average particle diameter is 250 mm for Pearlitol 300 DC, 360 mm for Pearlitol 400 DC and 520 mm for Pearlitol 500 DC.(27) See also Figure 3.

Table I: Pharmacopeial specifications for mannitol.

Test JP 2001 PhEur 2005 USP 28

Melting range 166–1698C 165–1708C 164–1698C

Specific rotation +1378 to +1458 +238 to +258 +1378 to +1458

Conductivity – 420 mS·cm—1 —

Acidity + — +

Loss on drying 40.3% 40.5% 40.3%

Chloride 40.007% — 40.007%

Sulfate 40.01% — 40.01%

Arsenic 41.3 ppm — 41 ppm

Lead – 40.5 ppm —

Nickel + 41 ppm —

Heavy metals 45 ppm — —

Reducing sugars + 40.2% +

Residue on ignition 40.10% — —

Related substances — 40.1% —

Bacterial endotoxins — 44 IU/g(a) —

Microbial — 4100/g —

contamination

Assay (dried basis) 5 98.0% 98.0–102.0% 96.0–101.5%

(a) Test applied only if the mannitol is to be used in the manufacture of parenteral dosage forms.

Mannitol 451

Table II: Solubility of mannitol.

Solvent Solubility at 208C

Alkalis Soluble

Ethanol (95%) 1 in 83

Ether Practically insoluble

Glycerin 1 in 18

Propan-2-ol 1 in 100

Water 1 in 5.5

Figure 1: Compression characteristics of granular mannitol (Pearlitol, Roquette Fre`res).

⃝: Pearlitol 300DC

□: Pearlitol 400DC Q: Pearlitol 500DC Tablet diameter: 20 mm

Lubricant: magnesium stearate 0.7% w/w for Pearlitol 400DC and Pearlitol 500DC; magnesium stearate 1% w/w for Pearlitol 300DC.

Refractive index: n20 = 1.333

Solubility: see Table II.

Specific surface area: 0.37–0.39 m2/g

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 effects.(28) 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 container in a cool, dry place.

Incompatibilities

Mannitol solutions, 20% w/v or stronger, may be salted out by potassium chloride or sodium chloride.(29) Precipitation has been reported to occur when a 25% w/v mannitol solution was allowed to contact plastic.(30) Sodium cephapirin at 2 mg/mL

and 30 mg/mL concentration is incompatible with 20% w/v aqueous mannitol solution. Mannitol is incompatible with xylitol infusion and may form complexes with some metals such as aluminum, copper, and iron. Reducing sugar impurities in mannitol have been implicated in the oxidative degradation of a peptide in a lyophilized formation.(31) Mannitol was found to reduce the oral bioavailability of cimetidine compared to sucrose.(32)

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.

Figure 2: Sorption–desorption isotherm for mannitol.

^: Sorption equilibrium moisture

&: Desorption equilibrium moisture

Figure 3: Particle size distribution of mannitol powder.

452 Mannitol

Safety as much calcium stearate is needed for lubrication of mannitol

Mannitol is a naturally occurring sugar alcohol found in

granulations than is needed for other excipients.

(38)

animals and plants; it is present in small quantities in almost all vegetables. Laxative effects may occur if mannitol is consumed orally in large quantities.(33) If it is used in foods as a bodying agent and daily ingestion of over 20 g is foreseeable, 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.(34)

A number of adverse reactions to mannitol have been reported, primarily following the therapeutic use of 20% w/v aqueous intravenous infusions.(35) 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- 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.(36)

LD50 (mouse, IP): 14 g/kg(37) LD50 (mouse, IV): 7.47 g/kg LD50 (mouse, oral): 22 g/kg LD50 (rat, IV): 9.69 g/kg LD50 (rat, oral): 13.5 g/kg

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.

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, powders and capsules; ophthalmic preparations; topical solu- tions). Included in nonparenteral and parenteral medicines licensed in the UK.

Related Substances

Sorbitol.

kywods

728x90

468x60.

mob

mercredi 6 novembre 2024

Aucun commentaire:

Enregistrer un commentaire

pop

slder

redect

push