Urea (chemical compound)

Urea, also known as carbamide, is a nitrogenous compound that is formed in vivo in the liver through the urea cycle, which converts ammonia into urea. It has a carbonyl group with two attached amine groups and contributes to osmotic balance in the kidneys by influencing the reabsorption of water and sodium during urine formation. It is the primary product of protein catabolism and encompasses a major component of urinary nitrogenous waste in all mammals and certain fish species. After it is formed in the liver, urea is carried in the blood to the kidneys, where it is removed in urine. Urea helps regulate the concentration of nitrogen waste in the body. Urine formation involves kidney filtration and hormonal control. Urea is also produced using laboratory techniques to supply larger amounts of the compound for industrial uses. Its colorless, crystalline structure allows urea to be an important compound in the fertilizer, feed, plastic, and pharmaceutical industries.

Background

In 1773, urea was first chemically separated from urine by French chemist Hilaire-Marin Rouelle. However, it was not until 1828 when the German chemist Friedrich Wöhler prepared urea from ammonium cyanate that the laboratory synthesis of a natural organic chemical compound demonstrated that organic compounds could be synthesized from inorganic materials. Urea is synthesized and prepared commercially from industrial-scale amounts of liquid ammonia and liquid carbon dioxide.

Urea is prepared from ammonia and carbon dioxide. Ammonia is produced through the Haber process, where nitrogen and hydrogen react in the presence of an iron catalyst. Ammonia and carbon dioxide are first fed into a high-pressure reactor to form urea in a two-step equilibrium reaction: ammonium carbamate (NH₂COONH₄) is first formed, followed by a dehydration step to produce urea and water. The reaction mixture contains unreacted ammonia, carbon dioxide, and ammonium carbamate. Reducing the pressure and supplying heat decays ammonium carbamate back to ammonia and carbon dioxide. In industrial settings, unreacted ammonia and carbon dioxide are recycled back to the reactor feed to minimize reactant waste and increase the overall production of ammonium carbamate and urea.

The manufacturing of urea uses compressed ammonia and carbon dioxide to increase urea production, while limiting by-product formation of biuret (NH₂CONHCONH₂). The compressed reactants first form ammonium carbamate through an exothermic reaction that releases heat. Two consecutive reactors then produce urea, where the products of the first reactor separate and purify the liquid before leading the gas products to the second reactor. The second reactor produces urea and recycles any unreacted carbon dioxide and ammonia solution to the initial inlet stream of the process.

Urea purification separates the major impurities, primarily water, from the urea production reaction and unreacted ammonia, carbon dioxide, and ammonium carbamate, in three flash stages. Flash separation stages partially vaporize the product to allow distinct separation between the unwanted liquid solution and the desired gas product. A lower pressure is used while heating the urea, allowing the ammonium carbamate to decompose back into ammonia and carbon dioxide. Water is recycled back to the second reactor, while excess ammonia is purified and returned to the inlet stream of the first reactor. Laboratory production of urea analyzes the various stages of granulation to determine the appropriate size distribution, adjusting the final urea size according to the size specifications of the company and the consumer. The final product is evaluated based on its moisture, biuret composition, formaldehyde composition, and pH.

Overview

The urea cycle for mammals is an essential metabolic process that converts toxic ammonia into urea by carrier molecules and enzymes within the liver. The first steps of the urea cycle occur in the mitochondria of liver cells, while the remaining steps take place in the cytoplasm. It is essential for the body to remove the nitrogenous waste because the build-up of ammonia is ultimately deadly. The term urea cycle disorder (UCD) describes a person’s inability to break down nitrogen-containing proteins and molecules. The severity of the disorder depends on a shortage of carbamoyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, and argininosuccinate lyase enzymes, as well as the absence of the cofactor producer N-acetylglutamate synthase in the urea cycle. Infants with severe UCD typically show signs of ailments shortly after birth, which can include cerebral edema, lethargy, anorexia, hyperventilation, hypoventilation, hypothermia, seizures, neurologic posturing, and coma. In patients with milder urea cycle disorders and arginase deficiency, ammonia accumulation rapidly develops following illness or stress. Urea cycle disorders increase the plasma ammonia concentration, though symptoms and clinically recognizable episodes are not visible for the first few months or decades of the disorder. The management of UCD manifestations can vary from restricting protein intake for two to twenty-four hours, to minimizing nitrogen consumption, to prescribing intravenous fluids and cardiac pressors. Some treatments also include drugs that help remove excess nitrogen from the body, such as sodium benzoate and phenylbutyrate.

Molecular and biochemical genetic testing is essential in the diagnosis of UCD. Plasma ammonia concentrations above 150 µmol/L, along with a normal anion gap and plasma glucose concentration, indicate the manifestation of UCD. Given the many varieties of UCD, additional plasma quantitative amino acid analyses and measurements of the urinary orotic acid must be performed to differentiate and distinguish particular disorders. Molecular genetic testing is capable of discerning specific urea cycle defects and, along with enzyme activity measurements, can confirm the specific defect of the patient.

The majority of the urea cycle disorders are hereditary. Genetic counselors aid in the molecular genetic testing and prenatal testing of candidate relatives to distinguish particular UCDs if the pathogenic deviations of the disorder are known. Identifying the candidate relatives to the disorder is essential, especially before manifestation and symptoms begin, to allow correct dietary therapy and other preventive measures for hyperammonemia.

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