Mannitol

Category

Diluent; Plasticizer; Sweetening Agents; Tablet and Capsule Diluent

Molecular Formula

C6H14O6

Molecular Weight

182.17

Grade

Pharmceutical Excipients

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 freeflowing 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.

UNII

3OWL53L36A

Chemical Name

D-Mannitol

CAS Number

69-65-8

Synonyms

Cordycepic acid; E421; Emprove; manna sugar; D-mannite; mannite; mannitolum; Mannogem; Pearlitol

Administration route

IP, IM, IV, and SC; infusions; buccal, oral and sublingual; ophthalmic; topical

Dosage Form

IP, IM, IV, and SC injections; infusions; buccal, oral and sublingual tablets, powders and capsules; ophthalmic preparations; topical solutions

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. 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.

Source and Preparation

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.

Applications

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. Mannitol may be used in direct-compression tablet applications, for which the granular and spray-dried forms are available, or in wet granulations. 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’. 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. 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 formulations, and as a carrier in dry powder inhalers. It is also used as a diluent in rapidly dispersing oral dosage forms. 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 gastrointestinal tract, but in large doses it can cause osmotic diarrhea.

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 may occur if mannitol is consumed orally in large quantities. 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.A number of adverse reactions to mannitol have been reported, primarily following the therapeutic use of 20% w/v aqueous intravenous infusions.(25) 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, hypersensitive-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. LD50 (mouse, IP): 14 g/kg 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

Incompatibilities

Mannitol solutions, 20% w/v or stronger, may be salted out by potassium chloride or sodium chloride. Precipitation has been reported to occur when a 25% w/v mannitol solution was allowed to contact plastic. 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. Mannitol was found to reduce the oral bioavailability of cimetidine compared to sucrose.