Hexamethylenetetramine

Absorption

After oral administration, rapid absorption of methenamine occurs. (1)

Toxicity

Less than 3.5% of patients treated with this drug will experience minor adverse events such as upset stomach, dysuria, nausea, and rash.

Description

Hexamethylenetetramine is a hardener in epoxy resins of the bisphenol A type and can also be used as an anticorrosive agent. It is a sensitizing agent in ceramics workers.

Chemical properties

White or almost white, crystalline powder or colourless crystals.

The Uses of Hexamethylenetetramine

Hexamethylenetetramine is a versatile reagent in organic synthesis. It is used in the Duff reaction, the Sommelet reaction, and in the Delepine reaction.

The Uses of Hexamethylenetetramine

Used in the treatment of urinary track infection.

The Uses of Hexamethylenetetramine

antibacterial, tuberculostatic

Indications

For prophylactic or suppressive treatment of frequently recurring urinary tract infections when long-term therapy is considered necessary. This drug is not used to treat infection and should only be used after appropriate eradication of infection with antimicrobial agents.

Background

Methenamine is a heterocyclic organic compound with a cage-like structure similar to adamantane. In salt form it is used for the treatment of urinary tract infection (Example: methenamine hippurate which is the hippuric acid salt of methenamine).

What are the applications of Application

Hexamethylenetetramine is a tetraamine compound with structural analogy to adamantane

Definition

ChEBI: A polycyclic cage that is adamantane in which the carbon atoms at positions 1, 3, 5 and 7 are replaced by nitrogen atoms.

Definition

A white crystalline organic compound made by condensing methanal with ammonia. It is used as a fuel for camping stoves, in vulcanizing rubber, and as a urinary disinfectant. Hexamine can be nitrated to make the high explosive cyclonite.

Preparation

Hexamethylenetetramine (also known as hexamine, hexa or HMT) is prepared from ammonia and formaldehyde:

Ammonia is passed into formalin at 20-30??C, with agitation. The resulting solution is evaporated under reduced pressure until most of the water is removed and the hexamethylenetetramine crystallizes. Yields of about 95% on both ammonia and formaldehyde can be achieved. Hexamethylenetetramine is a colourless crystalline solid which, on heating, sublimes with decomposition.

brand name

Uritone (Parke- Davis); Urotropin (Parke-Davis).

General Description

Odorless white crystalline powder or colorless lustrous crystals. Sublimes in a vacuum at about 505° F with some decomposition. Solutions are strong bases (pH of 0.2 molar aqueous solution is 8.4).

Air & Water Reactions

Highly flammable. Burns readily on contact with a flame with a smokeless flame. Finely powdered dust is significant dust explosion hazard. Water soluble.

Reactivity Profile

Hexamethylenetetramine is hygroscopic. Hexamethylenetetramine is sensitive to exposure to heat. Hexamethylenetetramine is incompatible with oxidizing agents. Hexamethylenetetramine is also incompatible with acids. Hexamethylenetetramine reacts violently with sodium peroxide. Hexamethylenetetramine reacts explosively with 1-bromopentaborane(9) at temperatures above 194° F. The complex with iodine deflagrates at 280° F. The 1:1 addition complex with iodoform has exploded at 352° F. Hexamethylenetetramine is corrosive to some metals, such as aluminum and zinc . Special Hazards of Combustion Products: Formaldehyde gas and ammonia may be given off when hot [USCG, 1999].

Hazard

Skin irritant. Flammable, dangerous fire risk.

Fire Hazard

Special Hazards of Combustion Products: Formaldehyde gas and ammonia may be given off when hot.

Flammability and Explosibility

Highly flammable

Pharmaceutical Applications

Methenamine (hexamine, hexamethylenetetraamine), under the name Urotropin, was successfully used in cystitis by the German physician Nicolaier in 1895. It has no intrinsic antibacterial activity and owes its effect to decomposition in acid conditions to formaldehyde, which is non-specifically microbicidal, and ammonia. It is often used in the form of organic acid salts, methenamine hippurate and methenamine mandelate, which have been claimed (unconvincingly) to keep the urinary pH low. Mandelic acid has some antibacterial activity in its own right and is sometimes given alone as a urinary antiseptic, usually as the calcium or ammonium salt. Infection with urea-splitting organisms such as Proteus spp. causes the urine to become alkaline and methenamine is unsuitable for these infections.
Methenamine is absorbed from the gut and mainly excreted unchanged in the urine, achieving concentrations of around 2–60 mg/L, sufficient to inhibit most bacteria and yeasts. Higher concentrations are achieved by the hippurate salt. It is given in enteric-coated tablets to prevent the liberation of formaldehyde by gastric acid. There is little breakdown in the blood and no systemic effect or toxicity.
Some patients complain of gastrointestinal upset or frequent and burning micturition. Attempts to control these side effects with alkali will abolish the antibacterial effect of the drug. Contact dermatitis and anterior uveitis have occasionally been encountered. Prolonged administration or high dosage may produce proteinuria, hematuria and bladder changes. Methenamine should not be given to patients with acidosis, gout or hepatic insufficiency. There have been fears about the potential carcinogenicity of formaldehyde.
Methenamine and its salts are unsuitable for the treatment of acute urinary tract infection. Their main use, now largely supplanted by other agents, has been in the long-term prophylaxis of recurrent cystitis.

Contact allergens

Hexamethylenetetramine is used in the foundry, tire and rubber, and phenol formaldehyde resins industries and in other applications such as a hardener in epoxy resins Bisphenol A type and as an anticorrosive agent. It is an ammonia and formaldehyde releaser sometimes used in topical medicaments and cosmetics

Pharmacokinetics

Ingestion of a 1-gram dose of methenamine hippurate produces antibacterial activity in the urine within 1/2 hour. Administration of 1 g twice daily produces continuous antibacterial activity in the urine.

Clinical Use

A venerable drug used for the disinfection of acidic urine, methenamine is a low-molecular-weight polymer of ammonia and formaldehyde that reverts to its components under mildly acidic conditions. Formaldehyde is the active antimicrobial component. Methenamine is used for recurrent urinary tract infections. The drug is available in various dosage forms as well as various salts, including the hippurate and mandelate.

Carcinogenicity

No significantly increased incidence of tumors was observed in rats or mice given HMTA for their lifetimes. Exposures in rats included 400 mg/day for 1 year, 10,000 ppm in drinking water for 2 years in each of three generations, 10,000 ppm in water for a lifetime (261), and up to 1000 ppm in the diet for 2 years. In mice, testing conditions included up to 10,000 ppm in drinking water for 60 weeks or 50,000 ppm for 30 weeks and a lifetime holding period, and up to 10,000 ppm in the diet for 2 years.
Injection of 25–30 g subcutaneously per mouse led to an increase in subcutaneous sarcomas in two experiments (418, 419) but not in two other studies. The relevance of this methodology to the workplace condition is questionable.

Metabolism

When in acidic urine (pH<6), methenamine is hydrolyzed to formaldehyde which acts as an antiseptic. (1)

Purification Methods

It is soluble in H2O (67%), CHCl3 (10%), EtOH (8%) and Et2O (0.3%), and a 0.2M solution has a pH of 8.4. Dissolve it in hot absolute EtOH (reflux, Norit), filter using a heated funnel, cool at room temperature first, then in ice. Wash the crystals with cold Et2O, dry them in air or under a vacuum. A further crop can be obtained by adding Et2O to the filtrate. It sublimes above 260o without melting. The picrate has m 179o(dec). [pK2 0 4.85: Reilley & Schmid Anal Chem 30 947 1958, pK2 0 6.30: Pummerer & Hofmann Chem Ber 56 1255 1923.] [Beilstein 26 I 306, 26 II 200, 26 III/IV 1680.]