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E 421

E 421 is a type of sugar alcohol used as a sweetener and medication.
E 421 is used as a low calorie sweetener as it is poorly absorbed by the intestines.
As a medication, E 421 is used to decrease pressure in the eyes, as in glaucoma, and to lower increased intracranial pressure.

CAS:    69-65-8
MF:    C6H14O6
MW:    182.17
EINECS:    200-711-8

Medically, E 421 is given by injection or inhalation.
Effects typically begin within 15 minutes and last up to 8 hours.

Common side effects from medical use include electrolyte problems and dehydration.
Other serious side effects may include worsening heart failure and kidney problems. 
E 421 is unclear if use is safe in pregnancy.
E 421 is in the osmotic diuretic family of medications and works by pulling fluid from the brain and eyes.

The discovery of E 421 is attributed to Joseph Louis Proust in 1806.
E 421 is on the World Health Organization's List of Essential Medicines.
E 421 was originally made from the flowering ash and called manna due to its supposed resemblance to the Biblical food.
E 421 is on the World Anti-Doping Agency's banned drug list due to concerns that it may mask other drugs.

A white, crystalline solid consisting of D-mannitol and a small quantity of E 421. 
E 421 is odorless and has a sweet taste. 
E 421 is soluble in water, very slightly soluble in alcohol, and practically insoluble in most other common organic solvents. 
E 421 is prepared commercially by catalytic reduction of glucose. 
E 421 occurs in small amounts in a variety of foods such as olives, beets, and celery, and in the exudate of certain trees.

E 421 is stable in the dry state and in aqueous solutions. 
E 421 may be sterilized by filtration or by autoclaving and if necessary may be autoclaved repeatedly with no adverse physical or chemical effects.
In solution, E 421 is not attacked by cold, dilute acids or alkalis, nor by atmospheric oxygen in the absence of catalysts. 
E 421 does not undergo Maillard reactions.
The bulk material should be stored in a well-closed container in a cool, dry place.

E 421 is a sugar alcohol that can be used as an inert osmotic control substance. 
The uptake and phosphorylation of E 421 is catalyzed by the mannitol-specific phosphoenolpyruvate-dependent phosphotransferase systems (PTS). 
E 421 can interact with neutrophils and monocytes. 
Experiments have shown that E 421 is able to decrease neutrophil apoptosis in vitro. 
The compound has been used in studies as a stimulator of cecal microbial growth and cellulolytic activity in rabbits. 
E 421 has been observed that mannitol can lower the fat digestibility and body fat accumulation in both normal and cecectomized rats, as well as upregulate monocyte HLA-DR, monocyte and neutrophil CD11b. 
Studies show that the E 421 is repressed by the transcription factor, mannitol operon repressor (MtlR) in Escherichia coli.

E 421 is a sugar alcohol occurring widely in plants and they are exudates, for example, in olive and plane trees (Collins, 2006). 
E 421 is produced commercially by the catalytic hydrogenation of fructose (Zelin, 2019). 
E 421 is used extensively in food and pharmaceutical industries because of its unique functional properties. 
E 421 is about 50% as sweet as sucrose and has a desirable cooling effect often used to mask bitter tastes. 
E 421 is non-cariogenic and has a low caloric content. 
E 421 is an osmotic diuretic that is metabolically inert in humans and is used for: the promotion of diuresis before irreversible renal failure becomes established, the promotion of urinary excretion of toxic substances, as an Antiglaucoma agent, and as a renal function diagnostic aid (O’Neil, 2013). 
Additonally, in 2020, E 421 was approved by the FDA as add-on maintenance therapy for the control of pulmonary symptoms associated with cystic fibrosis in adult patients (McKenna, 2020).

E 421 Chemical Properties
Melting point: 167-170 °C(lit.)
Boiling point: 295°C
Alpha: 141 º (c= USP-directives)
Density: 1.52
Refractive index: 1.3330 (estimate)
Fp: 290-295°C/3.5mm
Storage temp.: 2-8°C
Solubility H2O: 1 M at 20 °C, clear, colorless
Form: Crystalline Powder
pka: 13.5(at 18℃)
Color: White
PH: 5.0-6.5 (25℃, 1M in H2O)
Optical activity: [α]25/D +23.3 to +24.3°(lit.)
Water Solubility: soluble
λmax λ: 260 nm Amax: 0.04
λ: 280 nm Amax: 0.04
Merck: 14,5745
BRN: 1721898
Stability: Stable. Combustible. Incompatible with strong oxidizing agents.
InChIKey: FBPFZTCFMRRESA-KVTDHHQDSA-N
CAS DataBase Reference: 69-65-8(CAS DataBase Reference)
NIST Chemistry Reference: E 421 (69-65-8)
EPA Substance Registry System: E 421 (69-65-8)

E 421 is D-mannitol. 
E 421 is a hexahydric alcohol related to mannose and is isomeric with sorbitol.
E 421 occurs as a white, odorless, crystalline powder, or freeflowing granules. 
E 421 has a sweet taste, approximately as sweet as glucose and half as sweet as sucrose, and imparts a cooling sensation in the mouth. 
Microscopically, E 421 appears as orthorhombic needles when crystallized from alcohol. 
E 421 shows polymorphism.
White or almost white, crystalline powder or free-flowing granules.

Use
E 421 is widespread in plants and plant exudates; obtained from manna and seaweeds. 
E 421 is used in the food industry as anticaking and free-flow agent, flavo ring agent, lubricant and release agent, stabilizer and thickener and nutritive sweetener.
Used with boric acid in the manufacture of dry electrolytic condensers for radio applications; in making artificial resins and plasticizers; in pharmacy as excipient and diluent for solids and liqs; in analytical chemistry for boron determinations; in the manufacture of mannitol hexanitrate. 
E 421 used in the food industry as anticaking and free-flow agent, flavoring agent, lubricant and release agent, stabilizer and thickener and nutritive sweetener.

E 421 is widely used in pharmaceutical formulations and food products. 
In pharmaceutical preparations E 421 is primarily used as a diluent (10–90% w/w) in tablet formulations, where E 421 is of particular value since it is not hygroscopic and may thus be used with moisture-sensitive active ingredients.
E 421 may be used in direct-compression tablet applications,for which the granular and spray-dried forms are available, or in wet granulations.
Granulations containing E 421 have the advantage of being dried easily. 
Specific tablet applications include antacid preparations, glyceryl trinitrate tablets, and vitamin preparations. 

E 421 is commonly used as an excipient in the manufacture of chewable tablet formulations because of its negative heat of solution, sweetness, and ‘mouth feel’.
In lyophilized preparations, E 421 (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.
A pyrogen-free form is available specifically for this use. 
E 421 has also been used to prevent thickening in aqueous antacid suspensions of aluminum hydroxide (<7% w/v). 
E 421 has been suggested as a plasticizer in soft-gelatin capsules, as a component of sustained-release tablet formulations,and as a carrier in dry powder inhalers.
E 421 is also used as a diluent in rapidly dispersing oral dosage forms.
E 421 is used in food applications as a bulking agent. 

Therapeutically, E 421 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, E 421 is not absorbed significantly from the gastrointestinal tract, but in large doses it can cause osmotic diarrhea;

Medical uses
In the United States, E 421 is indicated for the reduction of intracranial pressure and treatment of cerebral edema and elevated intraocular pressure.
In the European Union, E 421 is indicated for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.

E 421 is used intravenously to reduce acutely raised intracranial pressure until more definitive treatment can be applied, e.g., after head trauma. 
While E 421 is the mainstay for treating high pressure in the skull after a bad brain injury, it is no better than hypertonic saline as a first-line treatment. 
In treatment-resistant cases, hypertonic saline works better.
Intra-arterial infusions of E 421 can transiently open the blood–brain barrier by disrupting tight junctions.

E 421 may also be used for certain cases of kidney failure with low urine output, decreasing pressure in the eye, to increase the elimination of certain toxins, and to treat fluid build up.

Intraoperative mannitol prior to vessel clamp release during renal transplant has been shown to reduce post-transplant kidney injury, but has not been shown to reduce graft rejection.

E 421 acts as an osmotic laxative in oral doses larger than 20 g, and is sometimes sold as a laxative for children.

The use of E 421, when inhaled, as a bronchial irritant as an alternative method of diagnosis of exercise-induced asthma has been proposed. 
A 2013 systematic review concluded evidence to support E 421's use for this purpose at this time is insufficient.

E 421 is commonly used in the circuit prime of a heart lung machine during cardiopulmonary bypass. 
The presence of E 421 preserves renal function during the times of low blood flow and pressure, while the patient is on bypass. 
The solution prevents the swelling of endothelial cells in the kidney, which may have otherwise reduced blood flow to this area and resulted in cell damage.

E 421 can also be used to temporarily encapsulate a sharp object (such as a helix on a lead for an artificial pacemaker) while it passes through the venous system. 
Because the E 421 dissolves readily in blood, the sharp point becomes exposed at its destination.

E 421 is also the first drug of choice to treat acute glaucoma in veterinary medicine. 
E 421 is administered as a 20% solution intravenously. 
E 421 dehydrates the vitreous humor and, therefore, lowers the intraocular pressure. 
However, E 421 requires an intact blood-ocular barrier to work.

Food
E 421 increases blood glucose to a lesser extent than sucrose is used as a sweetener for people with diabetes, and in chewing gums. 
Although E 421 has a higher heat of solution than most sugar alcohols, its comparatively low solubility reduces the cooling effect usually found in mint candies and gums. 
However, when E 421 is completely dissolved in a product, it induces a strong cooling effect.
Also, E 421 has a very low hygroscopicity – it does not pick up water from the air until the humidity level is 98%. 
This makes E 421 very useful as a coating for hard candies, dried fruits, and chewing gums, and it is often included as an ingredient in candies and chewing gum. 
The pleasant taste and mouthfeel of E 421 also makes it a popular excipient for chewable tablets.

Analytical chemistry
E 421 can be used to form a complex with boric acid. 
This increases the acid strength of the boric acid, permitting better precision in volumetric analysis of this acid.

Other
E 421 is the primary ingredient of mannitol salt agar, a bacterial growth medium, and is used in others.
E 421 is used as a cutting agent in various drugs that are used intranasally (snorted), such as cocaine. 
A mixture of E 421 and fentanyl (or fentanyl analogs) in ratio 1:10 is labeled and sold as "China white", a popular heroin substitute.

Manufacturing Process    
250 g of glucose is dissolved in distilled water to give a solution of 48% concentration. 
E 421 is heated to 65°C and barium hydroxide added in quantity sufficient to make the concentration of the barium hydroxide 0.2 mol/liter. 
E 421 is agitated and maintained at 65°C for 6 hours after the addition of the barium hydroxide. 
E 421 is then cooled and neutralized to a pH of 6.8 with sulfuric acid. 
The precipitated barium sulfate is filtered out. 

A quantity of activated supported nickel catalyst containing 5 g of nickel is added.
The slurry is introduced into a 3-liter rocking autoclave, and hydrogen admitted to a pressure of 1,500 psi. 
The autoclave is heated to a temperature of 150°C in one hour and held at this temperature for 2.5 hours more. 
Pressure rises to about 1,800 psi and then declines to about 1,600 during the hydrogenation. 
The autoclave is then cooled, emptied, and the catalyst filtered from the product. 
The filtrate is then concentrated under vacuum on a hot water bath to remove a part of the water.

The concentrate is taken up in warm aqueous E 421 so adjusted that the composition of the solvent is 90% methanol/10% water, and the weight of the solvent is 3 times the weight of the solids in the concentrate. 
E 421 is cooled to 20°C and held overnight. 
The E 421 which crystallizes is filtered out. 
The filtrate is concentrated on a water bath under vacuum to remove methanol and adjusted to a water percentage of 16%. 
The resulting syrup is viscous, noncrystallizing and nongelling, and analysis shows a PN (Pyridine Number) of 32 and essentially no reducing sugar, according to US Patent 2,749,371.

Synonyms
D-mannitol
mannitol
69-65-8
Mannite
Osmitrol
Manna sugar
87-78-5
Cordycepic acid
Osmofundin
Resectisol
D-(-)-Mannitol
Mannit
Osmosal
Mannazucker
Mannidex
Mannigen
Mannistol
Diosmol
Invenex
Isotol
Mannitol, D-
Marine Crystal
(2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol
Maniton-S
Mannogem 2080
(2R,3R,4R,5R)-Hexane-1,2,3,4,5,6-hexaol
Bronchitol
Mannitol (VAN)
Aridol
SDM No. 35
Hexahydroxyhexane
DL-Mannitol
NCI-C50362
Mannitol (USP)
Mannitol [USP]
BRN 1721898
CHEBI:16899
MFCD00064287
3OWL53L36A
INS NO.421
133-43-7
E-421
mannitol-d
INS-421
Mannitol 5%
NSC-407017
Mannitol [USAN]
1,2,3,4,5,6-Hexanehexol
Mannitol 10%
Mannitol 15%
Mannitol 20%
NCGC00164246-01
E421
Mannidex 16700
DSSTox_CID_3235
Osmitrol 5% In Water
DSSTox_RID_76936
Osmitrol 10% In Water
Osmitrol 15% In Water
Osmitrol 20% In Water
DSSTox_GSID_23235
287100-73-6
MTL
MANNITOL 25%
Resectisol In Plastic Container
Mannitol 5% In Plastic Container
Mannitol 10% In Plastic Container
Mannitol 15% In Plastic Container
Mannitol 20% In Plastic Container
CAS-69-65-8
Osmitrol (TN)
SMR000857324
CCRIS 369
HSDB 714
SR-01000838849
NSC 9256
EINECS 200-711-8
EINECS 201-770-2
OSMITROL 5% IN WATER IN PLASTIC CONTAINER
NSC 407017
OSMITROL 10% IN WATER IN PLASTIC CONTAINER
OSMITROL 15% IN WATER IN PLASTIC CONTAINER
OSMITROL 20% IN WATER IN PLASTIC CONTAINER
UNII-3OWL53L36A
Cordycepate
Mannitolum
Manitol
D-mitobronitol
MANNITOL 10% W/ DEXTROSE 5% IN DISTILLED WATER
AI3-19511
Maniton s
Mannit p
D-Mannit
D-?Mannitol
Bronchitol (TN)
(D)-mannitol
Mannitol 25
Mannitol 35
Mannitol 60
D(-)Mannitol
Mannitol,(S)
Pearlitol 25 c
Pearlitol 50 c
Mannitol m300
Pearlitol 160 c
Mannitol 200
Mannitol 300
Pearlitol 200 sd
Pearlitol 300 dc
Mannitol 2080
D-Mannitol (Osmitrol)
D-Mannitol (JP17)
MANNITOL [HSDB]
MANNITOL [INCI]
MANNITOL [FCC]
MANNITOL 15% W/ DEXTROSE 5% IN SODIUM CHLORIDE 0.45%
MANNITOL 5% W/ DEXTROSE 5% IN SODIUM CHLORIDE 0.12%
Crystalline mannitol fine
MANNITOL [II]
MANNITOL [MI]
D-[2-13C]Glucitol
MANNITOL [VANDF]
D-Mannitol, ACS reagent
D-Mannitol, >=98%
M0044
D-MANNITOL [JAN]
MANNITOL [MART.]
SCHEMBL919
bmse000099
CHEMBL689
Epitope ID:114705
MANNITOL [USP-RS]
MANNITOL [WHO-DD]
Isomalt impurity, mannitol-
Crystalline mannitol standard
D-MANNITOL [WHO-IP]
4-01-00-02841 (Beilstein Handbook Reference)
ED1D1E61-FEFB-430A-AFDC-D1F4A957FC3D
MLS001335977
MLS001335978
D-Mannitol, Biochemical grade
Crystalline mannitol extra-fine
MANNITOL [EP IMPURITY]
MANNITOL [ORANGE BOOK]
D-Mannitol, AR, >=99%
D-Mannitol, LR, >=99%
MANNITOL [EP MONOGRAPH]
DTXSID1023235
MANNITOL [USP MONOGRAPH]
DTXSID30858955
MANNITOLUM [WHO-IP LATIN]
HMS2230N11
AMY33410
HY-N0378
ZINC2041302
Tox21_112092
Tox21_201487
Tox21_300483
POTASSIUMNONAFLUORO-T-BUTOXIDE
AKOS006280947
D-Mannitol, plant cell culture tested
Tox21_112092_1
BCP9000575
CCG-266445
D-Mannit 1000 microg/mL in Methanol
D-Mannitol, BioXtra, >=98% (GC)
DB00742
D-Mannitol, NIST(R) SRM(R) 920
ISOMALT IMPURITY B [EP IMPURITY]
NCGC00164246-03
NCGC00164246-04
NCGC00164246-05
NCGC00254277-01
NCGC00259038-01
85085-15-0
AC-12776
AC-14054
AS-30501
D-Mannitol, tested according to Ph.Eur.
D-Mannitol, p.a., 96.0-101.5%
D-Mannitol, SAJ first grade, >=99.0%
SORBITOL-MANNITOL COMPONENT MANNITOL
D-Mannitol, SAJ special grade, >=99.0%
E 421
S2381
SW220287-1
MANNITOL COMPONENT OF SORBITOL-MANNITOL
C00392
D00062
EN300-212188
AB00443917_06
065M361
ISOMALT IMPURITY, MANNITOL- [USP IMPURITY]
Q407646
WURCS=2.0/1,1,0/[h1122h]/1/
Q-101039
SR-01000838849-3
SR-01000838849-4
D-Mannitol, ACS reagent, for microbiology, >=99.0%
LACTITOL MONOHYDRATE IMPURITY C [EP IMPURITY]
rel-(2R,3R,4R,5R)-Hexane-1,2,3,4,5,6-hexaol
D-Mannitol, meets EP, FCC, USP testing specifications
Mannitol, European Pharmacopoeia (EP) Reference Standard
Z1198149813
D-Mannitol, BioUltra, >=99.0% (sum of enantiomers, HPLC)
Mannitol, United States Pharmacopeia (USP) Reference Standard
D-Mannitol, >=99.9999% (metals basis), for boron determination
Mannitol, Pharmaceutical Secondary Standard; Certified Reference Material

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