NIACINAMIDE

Synonyms;

Niacinamide; Nicotinic amide; 3-pyridinecarboxamide; beta-pyridinecarboxamide; niacin; vitamin B3; pyridine-3-carboxamide; Vi-Nicotyl; Nicofort; Nicosylamide; Nicotililamido; Nicamina; Niko-tamin; Acid amide; Delonin Amide; Niamide; Nictoamide; Nicovit; Nicobion; Nicotine amide; Nicotinsaureamid; Witamina PP; Pelmine; Propamine A; Nicotol; Nicotylamide; Hansamid; Dipigyl; Nicogen; Nicotinamidum; Amixicotyn; Niavit PP; Dipegyl; Nicovitina; Niacevit; NAM; Amid kyseliny nikotinove; Nicotine acid amide; Nicota; Papulex; Pyridine-3-carboxylic acid amide; Nicotamide; Nandervit-N; Factor pp; Nicotinamida; Nicomidol; Austrovit PP; Amide PP; b-Pyridinecarboxamide; Nicotylamidum; Nicotilamide; Pelonin amide; Niocinamide; Nicozymin; Benicot; Nicovel; Nicosan 2; Inovitan PP; Endobion; PP-Faktor; Niozymin; Nicamindon; Aminicotinm-(Aminocarbonyl)pyridine; Pelmin; Nicovitol; 3-Carbamoylpyridine, Savacotyl; Nicamide; Vi-noctyl; Mediatric; Nicasir; 3-Pyridinecarboxylic acid amide; Amnicotin; Nicotinamide

Molecular Formula: C6H6N2O

Melting Point: 128-131℃

Boling Point: 150-160℃

Flash Point: 182℃

Nicotinamide (NAM), also known as niacinamide, is a form of vitamin B3 found in food and used as a dietary supplement and medication. It is a white powder or crystalline solid. It is odorless and has a bitter taste. It is very soluble in water. Niacinamide is present in all living cells and it is essential for normal growth and health. Niacinamide is used as a dietary supplement and medication. It is also used in personal care products. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (niacin) may be used for this purpose, niacinamide has the benefit of not causing skin flushing. As a cream, it is used to treat acne. It is a water soluble vitamin.

Side effects are minimal. At high doses liver problems may occur. Normal amounts are safe for use during pregnancy. Niacinamide is in the vitamin B family of medications, specifically the vitamin B3 complex. It is an amide of nicotinic acid. Foods that contain niacinamide include yeast, meat, milk, and green vegetables.

Niacinamide was discovered between 1935 and 1937. It is on the World Health Organization's List of Essential Medicines. Niacinamide is available as a generic medication and over the counter.[8] Commercially, niacinamide is made from either nicotinic acid or nicotinonitrile. In a number of countries grains have niacinamide added to them.

In humans, niacinamide is required for lipid metabolism, tissue respiration, and glycogenolysis. In vivo, niacinamide is formed from conversion of niacin. In addition, some dietary tryptophan is oxidized to niacin and then to niacinamide in vivo. Niacinamide is incorporated into 2 coenzymes: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP act as hydrogen-carrier molecules in glycogenolysis, tissue respiration, and lipid metabolism.

Niacinamide is efficiently absorbed from the gastrointestinal tract. At low doses, absorption is mediated via sodium-dependent facilitated diffusion. Passive diffusion is the principal mechanism of absorption at higher doses. Doses of up to three to four grams of niacinamide are almost completely absorbed. Niacinamide is transported via the portal circulation to the liver and via the systemic circulation to the various tissues of the body. Niacinamide enters most cells by passive diffusion and enters erythrocytes by facilitated transport. We can claim that niacinamide is widely distributed /throughout/ body tissues.

Niacinamide is widely in use of medical areas.

We mentioned before that niacinamide is the preferred treatment for pellagra, caused by niacin deficiency. While niacin may be used, niacinamide has the benefit of not causing skin flushing. Niacinamide cream is used as a treatment for acne. It has anti-inflammatory actions, which may benefit people with inflammatory skin conditions. Niacinamide increases the biosynthesis of ceramides in human keratinocytes in vitro and improves the epidermal permeability barrier in vivo. The application of 2% topical niacinamide for 2 and 4 weeks has been found to be effective in lowering the sebum excretion rate.  Niacinamide has been shown to prevent Cutibacterium acnes-induced activation of toll-like receptor 2, which ultimately results in the down-regulation of pro-inflammatory interleukin-8 production. Niacinamide at doses of 500 to 1000 mg a day decreases the risk of skin cancers, other than melanoma, in those at high risk. Also niacinamide, at doses of 500 to 1000 mg a day decreases the risk of skin cancers, other than melanoma, in those at high risk. At high doses (up to 3.5 g/day), niacinamide is protective against cell death and inhibits the production of inflammatory mediators in animal and in in vitro models of oxidant-induced cell injury.

To understand the niacianmide cream more effectively, there was a research made on female rats.  14(C)Niacinamide was incorporated into an oil-in-water (o/w) skin cream and into a 30% (w/w) soap base and applied to the skin of female Colworth Wistar rats. The final concentration of niacinamide in the soap solution was approximately 0.3% (w/v) and was 1% (w/w) in the skin cream. Application of the skin cream and soap paste was made to rat skin at approximately 20 mg/sq cm. The cream was carefully massaged over 10 sq cm of skin for up to 5 min before covering with polythene-lined occlusive protective patches. The rats were placed in metabolism cages for 48 hr during which time all excreta was collected. At 48 hr, the animals were killed and the patch, carcass, and treated area of skin were assayed for 14(C). Up to 32% 14(C) was recovered in excreta and in the carcasses from rats treated with skin cream containing 14(C)Niacinamide and up to 30% from those treated with soap paste.

Addition to all of these use areas, niacinamide has minimal side effects. At high doses liver problems may occur. Normal doses are safe during pregnancy.

Niacinamide on metabolism goes as following;

Niacinamide methylation followed by urinary excretion of N-methylnicotinamide increases in cirrhotic patients, despite the derangement of the overall methylation processes in liver disease. The rise in N-methylnicotinamide could depend, at least in part, on a reduced transformation of this molecule into 2-pyridone-5-carboxamide. Serum and urinary levels (mean +/- SEM) of N-methylnicotinamide and urinary excretion of 2-pyridone-5-carboxamide were measured in 10 healthy controls and 10 patients with liver cirrhosis in basal conditions and after a nicotinamide oral load (1.5 mg/kg body weight). N-methylnicotinamide serum levels increased significantly (p < 0.01) in cirrhotic patients compared to controls, both as basal values (0.43 +/- 0.07 nmol/ml; 0.15 +/- 0.01) and as area under the curve 5 hr after a niacinamide load (cirrhotics: 562.4 +/- 50.5 nmol/mL x min; controls: 314.4 +/- 23.8). Twenty-four-hour urinary excretion of N-methylnicotinamide and 2-pyridone-5-carboxamide was also significantly (p < 0.05) increased in cirrhotic patients versus controls, both in basal conditions (N-methylnicotinamide: 82.0 +/- 8.4 umol, 48.8 +/- 4.8; 2-pyridone-5-carboxamide: 129.3 +/- 23.0, 64.6 +/- 9.8) and after a niacinamide oral load (N-methylnicotinamide: 290.1 +/- 23.1, 180.8 +/- 7.4; 2-pyridone-5-carboxamide: 694.7 +/- 32.5, 391.0 +/- 21.9). Moreover, 24 hr N-methylnicotinamide/2-pyridone-5-carboxamide ratio was similar in patients and controls (basal: 0.78 +/- 0.39, 0.90 +/- 0.51; load: 0.42 +/- 0.11, 0.48 +/- 0.16). In cirrhotic patients nicotinamide methylation is increased, as shown by the rise in urinary N-methylnicotinamide and 2-pyridone-5-carboxamide that is concurrent and proportional (constant 24-hr metabolite ratio), deriving from the catabolic state of cirrhosis.

The identification of nicotinamide-N1-oxide as a metabolite in the urine of a schizophrenic patient prompted a study of the relative metabolism of nicotinic acid and nicotinamide in mental patients and healthy volunteers. Metabolites quantified included N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide, N1-methylnicotinamide, nicotinuric acid, and nicotinamide-N1-oxide. More of most of these metabolites evidently was excreted after nicotinamide ingestion than after nicotinic acid. At the highest doses (3000 mg/day), the relative proportions of these metabolites in the urine were changed. There were only slight difference between healthy individuals and mental patients in the quantities of metabolites excreted, and no statistically significant trends were noted.

Niacinamide’s roles in chemistry in general are like following,

The structure of niacinamide consists of a pyridine ring to which a primary amide group is attached in the meta position. It is an amide of nicotinic acid. As an aromatic compound, it undergoes electrophilic substitution reactions and transformations of its two functional groups. Examples of these reactions reported in Organic Syntheses include the preparation of 2-chloronicotinonitrile by a two-step process via the N-oxide, from nicotinonitrile by reaction with phosphorus pentoxide, and from 3-aminopyridine by reaction with a solution of sodium hypobromite, prepared in situ from bromine and sodium hydroxide.

Industrial Production wise, the hydrolysis of niacinamide is catalysed by the enzyme nitrile hydratase from Rhodococcus rhodochrous J1, producing 3500 tons per annum of niacinamide for use in animal feed. The enzyme allows for a more selective synthesis as further hydrolysis of the amide to nicotinic acid is avoided. Niacinamide can also be made from nicotinic acid. According to Ullmann's Encyclopedia of Industrial Chemistry, worldwide 31,000 tons of niacinamide were sold in 2014.

In biochemistry specifically, niacinamide, as a part of the cofactor niacinamide adenine dinucleotide (NADH / NAD+) is crucial to life. In cells, niacinamide is incorporated into NAD+ and niacinamide  adenine dinucleotide phosphate (NADP+). NAD+ and NADP+ are cofactors in a wide variety of enzymatic oxidation-reduction reactions, most notably glycolysis, the citric acid cycle, and the electron transport chain. If humans ingest niacinamide, it will likely undergo a series of reactions that transform it into NAD, which can then undergo a transformation to form NADP+. This method of creation of NAD+ is called a salvage pathway. However, the human body can produce NAD+ from the amino acid tryptophan and niacin without our ingestion of niacinamide. NAD+ acts as an electron carrier that helps with the interconversion of energy between nutrients and the cell's energy currency, adenosine triphosphate (ATP). In oxidation-reduction reactions, the active part of the cofactor is the niacinamide. In NAD+, the nitrogen in the aromatic niacinamide ring is covalently bonded to adenine dinucleotide. The formal charge on the nitrogen is stabilized by the shared electrons of the other carbon atoms in the aromatic ring. When a hydride atom is added onto NAD+ to form NADH, the molecule loses its aromaticity, and therefore a good amount of stability. This higher energy product later releases its energy with the release of a hydride, and in the case of the electron transport chain, it assists in forming adenosine triphosphate. When one mole of NADH is oxidized, 158.2 kJ of energy will be released. Also, niacinamide occurs as a component of a variety of biological systems, including within the vitamin B family and specifically the vitamin B3 complex. It is also a critically important part of the structures of NADH and NAD+, where the N-substituted aromatic ring in the oxidised NAD+ form undergoes reduction with hydride attack to form NADH. The NADPH/NADP+ structures have the same ring, and are involved in similar biochemical reactions. Also, niacinamide, via its major metabolite NAD+ (nicotinamide adenine dinucleotide), is involved in a wide range of biological processes, including the product of energy, the synthesis of fatty acids, cholesterol and steroids, signal transduction and the maintenance of the integrity of the genome.

Addition to these, researches show that a 2015 trial found niacinamide to reduce the rate of new nonmelanoma skin cancers and actinic keratoses in a group of people at high risk for the conditions.

Niacinamide has been investigated for many additional disorders, including treatment of bullous pemphigoid nonmelanoma skin cancers. It may be beneficial in treating psoriasis. There is tentative evidence for a potential role of niacinamide in treating acne, rosacea, autoimmune blistering disorders, ageing skin, and atopic dermatitis. Niacinamide also inhibits poly(ADP-ribose) polymerases (PARP-1), enzymes involved in the rejoining of DNA strand breaks induced by radiation or chemotherapy. ARCON (accelerated radiotherapy plus carbogen inhalation and niacinamide) has been studied in cancer.

HIV Research has suggested niacinamide may play a role in the treatment of HIV.

Manufacturing;

Workers who use niacinamide may breathe in vapors or have direct skin contact. The general population may be exposed by consumption of food and administration of medications. If niacinamide is released to the environment, it will be broken down in air. It is expected to be broken down by sunlight. It will not move into air from moist soil and water surfaces. It is expected to move through soil. It will be broken down by microorganisms, and is not expected to build up in fish. RISK: Niacinamide is a Generally Regarded As Safe (GRAS) chemical at levels found in consumer products, and has a low risk of toxicity in humans. Nausea was reported in volunteers exposed once to a low oral dose of niacinamide. No evidence of liver or kidney toxicity were observed in diabetic and at-risk-of-diabetes patients taking moderate oral doses of niacinamide for several years. Eye irritation was observed following direct exposure to laboratory animals. Allergic skin reactions were not observed following repeated skin exposure. Decreased body weights and mild liver effects were observed following repeated exposure to moderate-to-high oral doses. Altered behavior was reported in laboratory animals at very high oral doses. Accelerated development of diabetes was observed in diabetic-prone laboratory animals following repeated exposure to niacinaide. Data on the potential for niacinamide to cause infertility in laboratory animals were not available. No evidence of abortion or birth defects was observed in laboratory animals exposed to niacinamide  during pregnancy. However, decreased offspring body weight and altered bone development were observed at high oral doses that also made the mothers sick. Tumors were not induced in laboratory animals following lifetime oral exposure to niacinamide. However, co-exposure to niacinamide increased the number of kidney tumors induced by the known cancer agent diethylnitrosamine. The potential for niacinamide to cause cancer in humans has not been assessed by the U.S. EPA IRIS program, the International Agency for Research on Cancer, or the U.S. National Toxicology Program 14th Report on Carcinogens. (SRC)

There are  few options on methods of manufacturing;

• 2-Methylglutaronitrile, a byproduct of adiponitrile production, is converted to 2-methyl-1,5-diaminopentane. Cyclic hydrogenation gives 3-methylpiperidine. Dehydrogenation yields 3-methylpyridine, which is then ammoxidated and partly hydrolyzed to niacinamide.
• In a multitubular reactor 3-methylpyridine, air, ammonia, and hydrogen react at ca. 350 °C and moderate pressure to give 3-cyanopyridine. Heterogeneous catalysts containing oxides of antimony, vanadium, and titanium, antimony, vanadium, and uranium or antimony-vanadium-titanium catalyst are highly effective. For instance, with a vanadium, titanium, zirconium, molybdenum catalyst, a reactor temperature of 340 °C, and a molar feed ratio of 3-methylpyridine:ammonia: oxygen of 1:1.3:40 yields 95% of 3-cyanopyridine. 3-Cyanopyridine is converted to niacinamide by alkaline hydrolysis. This reaction has the advantage that saponification to the amide is fast compared to total hydrolysis to nicotinic acid. The hydrolysis to the amide is normally carried out with catalytic amounts of bases, mainly sodium hydroxide, at 130-150 °C.
• In the Lonza process, 3-cyanopyridine is converted to niacinamide by means of an immobilized microorganism of the genus Rhodococcus. Heterogeneous catalysts are also mentioned. A copper-chromium oxide catalyst, manganese dioxide, or manganese dioxide with chromium-nickel oxide, chromium-cobalt oxide, or manganese dioxide with titanium-silicon dioxide give good yields of niacinamide.
• Nicotinic acid is melted and reacted with ammonia gas to yield niacinamide. The reaction is catalyzed by the presence of ammonium salts. After distillation, niacinamide is dissolved in water, purified by the addition of activated carbon, filtered, recrystallized and centrifuged. The niacinamide contained in the mother liquor is reclaimed by a special recovery operation. The wet pure niacinamide filter cake is dried under vacuum in a rotary vacuum drier.
• A buffered solution of 3-cyanopyridine in water is hydrolyzed to niacinamide in the presence of a catalyst. The resulting solution is purified over activated carbon, filtered and then concentrated in a evaporator. The concentrated niacinamide solution is dried under vacuum.
• Preparation from 3-cyanopyridine: E.J.Gasson, D.J. Hadley, United States of America patent 2904552 (1959 to Distillers). Alternately prepared by passing ammonia gas into molten nicotinic acid: A. Truchan, J.B. Davidson, United States of America patent 2993051 (1961 to Cowles Chem.).

Environmental Summary;

Niacinamide's production and use as a dietary supplement and administration as a medicine and in cosmetics as a hair and skin conditioning agent may result in its release to the environment through various waste streams. Niacinamide (vitamin B3) is a precursor of the coenzymes NAD and NADP. If released to air, an estimated vapor pressure of 4.2X10-4 mm Hg at 25 °C indicates niacinamide will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase niacinamide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 6 days. Particulate-phase niacinamide will be removed from the atmosphere by wet or dry deposition. Niacinamide absorbs UV light at wavelengths >300 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, niacinamide is expected to have very high mobility based upon an estimated Koc of 15. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.9X10-12 atm-cu m/mole. Niacinamide was determined to be readily biodegradable in an aerobic screening test, suggesting that biodegradation may be an important environmental fate process in soil and water. If released into water, niacinamide is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. Hydrolysis is not expected to be an important environmental fate process since amides hydrolyze slowly under environmental conditions. Occupational exposure to niacinamide may occur through inhalation of dust and dermal contact with this compound at workplaces where niacinamide is produced or used. Monitoring data indicate that the general population may be exposed to niacinamide via ingestion of food, smoking cigarettes and dermal contact with consumer products containing this compound. Exposure to niacinamide will also occur by direct medical treatment. (SRC)