1 Mannitol1 Nonproprietary NamesBP: MannitolJP:D-MannitolPhEur: MannitolUSP NF: Mannitol2 SynonymsCompressol; Cordycepic acid;C*PharmMannidex; E421;Emprove;Ludiflash; manita; manitol; manna sugar; mannit;D-mannite; mannite; mannitolum;Mannogem; Chemical Name and CAS Registry NumberD-Mannitol [69-65-8]4 Empirical Formula and Molecular Structural Formula6 Functional CategoryLyophilization aidplasticizing agent; sweetening agent; tablet andcapsule diluent; tonicity Applications in Pharmaceutical Formulation orTechnologyMannitol is widely used in Pharmaceutical formulations and foodproducts.
2 In Pharmaceutical preparations it is primarily used as adiluent (10 90% w/w) in tablet formulations, where it is ofparticular value since it is not hygroscopic and may thus be usedwith moisture-sensitive active ingredients.(1,2)Mannitol may be used in direct-compression tablet applica-tions,(3,4)for which the granular and spray-dried forms areavailable,(5)or in wet granulations.(6,7)Granulations containingmannitol have the advantage of being easily dried. Specific tabletapplications include antacid preparations, glyceryl trinitrate tablets,and vitamin preparations. Mannitol is commonly used as anexcipient in the manufacture of chewable tablet formulationsbecause of its negative heat of solution, sweetness, and mouthfeel.
3 (7,8)It is also used as a diluent in rapidly dispersing oral dosageforms.(9,10)Mannitol has been used to prevent thickening in aqueous antacidsuspensions of aluminum hydroxide (<7% w/v). It has also beenused as a plasticizer in soft-gelatin capsules, as a component ofsustained-release tablet formulations,(11)as a carrier in dry powderinhalers,(12,13)and as a diluent in rapidly dispersing oral dosageforms.(14,15)In lyophilized preparations, mannitol (20 90% w/w) has beenused as a carrier to produce a stiff, homogeneous cake that improvesthe appearance of the lyophilized plug in a vial.
4 (16 18)A pyrogen-free form is available specifically for this is used in food applications as a bulking DescriptionMannitol isD-mannitol. It is a hexahydric alcohol related tomannose and is isomeric with occurs as a white, odorless, crystalline powder, or free-flowing granules. It has a sweet taste, approximately as sweet asglucose and half as sweet as sucrose, and imparts a coolingsensation in the mouth. Microscopically, it appears as orthorhom-bic needles when crystallized from alcohol. Mannitol showspolymorphism.(19)9 Pharmacopeial SpecificationsSeeTable alsoSection Typical PropertiesCompressibilityseeFigure 1:Excipient: mannitol; manufacturer: Merck; magnification: 50 ;voltage: 2:Excipient: mannitol; manufacturer: Merck; magnification: 500 ;voltage: (bulk) g/cm3for powder; g/cm3for (tapped) g/cm3for powder.
5 G/cm3for (true) g/cm3 Dissociation constantpKa= at 188 CFlash point<1508 CFlowabilityPowder is cohesive, granules are free of ( kcal/g)Heat of solution J/g ( cal/g) at 258 CMelting point166 1688 CMoisture contentseeFigure w/v aqueous solution is isoosmotic size distributionPearlitol 300 DC: maximum of greater than 500mm andminimum of 90% greater than 200mm in size;Pearlitol 400 DC: maximum of 20% greater than 500mm andminimum of 85% greater than 100mm in size;Pearlitol 500 DC: maximum of greater than 841mm andminimum of 90% greater than 150mm in particle diameter is 250mm forPearlitol 300 DC,360mm forPearlitol 400 DCand 520mm forPearlitol 500DC.
6 (20)See alsoFigure indexnD20= surface m2/gSEM 3:Excipient: mannitol powder; manufacturer: SPI Polyols Inc.; lot no:3140G8; magnification: 100 .SEM 4:Excipient: mannitol granular; manufacturer: SPI Polyols Inc.; lotno: 2034F8; magnification: 100 .Table I:Pharmacopeial specifications for XVPhEur NF30 Identification Characters Appearance ofsolution Melting range 166 1698C165 1708C164 1698 CSpecific rotation 1378to 1458 238to 258 1378to 1458 Conductivity 20mS cm 1 Acidity Loss on drying 1ppmLead Nickel 1ppm Heavy metals 5ppm Reducing sugars Residue onignition Relatedsubstances Bacterialendotoxins(a) 4IU/g(b) (c)Microbialcontamination 100cfu/g Assay (driedbasis) (a) Test applied only if the mannitol is to be used in the manufacture of parenteraldosage forms.
7 (b) For parenteral preparations having a concentration of 100g/L or less of mannitol.(c) For parental preparations having a concentration of more than 100g/L of force (kN)Tablet crushing strength (N)403020100201030405080706090100 Pearlitol 500 DCPearlitol 400 DCPearlitol 300 DCFigure 1:Compression characteristics of granular mannitol (Pearlitol,Roquette Fre`res).Tablet diameter: 20mm. Lubricant: magnesium stearate w/w forPearlitol 400 DCandPearlitol 500 DC; magnesium stearate 1% w/w forPearlitol 300 spectraseeFigure spectraseeFigure Stability and Storage ConditionsMannitol is stable in the dry state and in aqueous may be sterilized by filtration or by autoclaving and ifnecessary may be autoclaved repeatedly with no adverse physical orchemical effects.
8 (22)In solution, mannitol is not attacked by cold,dilute acids or alkalis, nor by atmospheric oxygen in the absence ofcatalysts. Mannitol does not undergo Maillard bulk material should be stored in a well-closed container in acool, dry IncompatibilitiesMannitol solutions, 20% w/v or stronger, may be salted out bypotassium chloride or sodium chloride.(23)Precipitation has beenreported to occur when a 25% w/v mannitol solution was allowedto contact plastic.(24)Sodium cephapirin at 2mg/mL and 30 mg/mLconcentration is incompatible with 20% w/v aqueous mannitolsolution. Mannitol is incompatible with xylitol infusion and mayform complexes with some metals such as aluminum, copper, andiron.
9 Reducing sugar impurities in mannitol have been implicated inthe oxidative degradation of a peptide in a lyophilized forma-tion.(25)Mannitol was found to reduce the oral bioavailability ofcimetidine compared to sucrose.(26)13 Method of ManufactureMannitol may be extracted from the dried sap of manna and othernatural sources by means of hot alcohol or other selective is commercially produced by the catalytic or electrolytic reductionof monosaccharides such as mannose and humidity (%)Moisture content (%)43332342610812 Sorption equilibrium moistureDesorption equilibrium moistureFigure 2:Sorption desorption isotherm for size = 88 m80 Particle diameter ( m)Weight oversize (%)40020408060100 Figure 3:Particle size distribution of mannitol II.
10 Solubility of at 208 CAlkalisSolubleEthanol (95%)1 in 83 EtherPractically insolubleGlycerin1 in 18 Propan-2-ol1 in 100 Water1 in (KM units) 4:Infrared spectrum of mannitol measured by diffuse with permission of Informa [2nd deriv. log(1/R)]Wavelength/nm1100 (1/R) 5:Near-infrared spectrum of mannitol measured by SafetyMannitol is a naturally occurring sugar alcohol found in animalsand plants; it is present in small quantities in almost all effects may occur if mannitol is consumed orally in largequantities.(27)If it is used in foods as a bodying agent and dailyingestion of over 20 g is foreseeable, the product label should bearthe statement excessive consumption may have a laxative effect.