Isoniazid CAS 54-85-3
Introduction：Basic information about Isoniazid CAS 54-85-3, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Isoniazid Basic information
| Product Name: | Isoniazid |
| Synonyms: | 4-PYRIDINECARBOHYDRAZIDE;4-PYRIDINECARBOXYLIC ACID HYDRAZIDE;AKOS BBS-00004103;Isoteb;4-PYRIDINECARBOXYLIC ACID HYDRAZIDE FOR;Isonicotinyl hydrazid;Isoniazid Vetec(TM) reagent grade, 98%;HYCOZID |
| CAS: | 54-85-3 |
| MF: | C6H7N3O |
| MW: | 137.14 |
| EINECS: | 200-214-6 |
| Product Categories: | AMIDE;Amines;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;Antituberculotic;API;NYDRAZID;bc0001;54-85-3 |
| Mol File: | 54-85-3.mol |
Isoniazid Chemical Properties
| Melting point | 171-173 °C (lit.) |
| Boiling point | 251.97°C (rough estimate) |
| density | 1.2620 (rough estimate) |
| bulk density | 800kg/m3 |
| refractive index | 1.6910 (estimate) |
| Fp | >250°C |
| storage temp. | 2-8°C |
| solubility | 125g/l |
| form | Crystals or Crystalline Powder |
| pka | pKa 2.00/3.60/10.8(H2O) (Uncertain) |
| color | White or colorless |
| PH | 6-8 (50g/l, H2O, 20℃) |
| Odor | Odorless |
| PH Range | 5.5 - 6.5 at 10 g/l at 25 °C |
| Water Solubility | 14 g/100 mL (25 ºC) |
| Sensitive | Air Sensitive |
| Merck | 14,5186 |
| BRN | 119374 |
| BCS Class | 1,3 |
| Stability: | Stability Stable, but may be air or light sensitive. Combustible. Incompatible with strong oxidizing agents, chloral, aldehydes, iodine, ferric salts, hypochlorites. |
| Major Application | forensics and toxicology pharmaceutical (small molecule) |
| InChI | 1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10) |
| InChIKey | QRXWMOHMRWLFEY-UHFFFAOYSA-N |
| SMILES | NNC(=O)c1ccncc1 |
| CAS DataBase Reference | 54-85-3(CAS DataBase Reference) |
| NIST Chemistry Reference | Isoniazid(54-85-3) |
| IARC | 3 (Vol. 4, Sup 7) 1987 |
| EPA Substance Registry System | Isoniazid (54-85-3) |
Safety Information
| Hazard Codes | Xn |
| Risk Statements | 22-38-40-36/37/38 |
| Safety Statements | 37-36/37/39-26 |
| RIDADR | 2811 |
| WGK Germany | 3 |
| RTECS | NS1751850 |
| TSCA | TSCA listed |
| PackingGroup | III |
| HS Code | 29333999 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Acute Tox. 4 Oral Skin Irrit. 2 |
| Hazardous Substances Data | 54-85-3(Hazardous Substances Data) |
| Toxicity | LD50 in mice (mg/kg): 151 i.p., 149 i.v. (Jenney, Pfeiffer) |
| Description | Isoniazid, the hydrazide of isonicotinic acid was introduced into medical practice for treating tuberculosis in 1953. Isoniazid exhibits bactericidal action on Mycobacterium tuberculosis. It inhibits the synthesis of mycolic acid, an important component of the cellmembrane of mycobacteria. Mycolic acid is specific only to mycobacteria, and it is thecause of the selective toxicity of the drug with respect to these microorganisms. Mutants that are resistant to isoniazid are rarely seen in nature, and in a spontaneouslygrowing population of tuberculous bacillus there is approximately one mutant in every105–106 organisms. Large populations of microorganisms of the order 109–1010 bacilli inthe pulmonary cavities contain a significant number of resistant mutants. If only isoniazidis taken during treatment, an increased number of mutants will be observed and they willeventually become the dominant phenotype. The transformation from sensitive to nonsensitive microorganisms during treatment is called secondary or acquired resistance, whichcan originate over the course of a few weeks. Isoniazid is the most important drug for treating pulmonary and nonpulmonary forms of tuberculosis. It is active against both intracellular and extracellular organisms. In order to prevent secondary resistance, isoniazidshould be used with other effective drugs (usually rifampin). Synonyms of this drug aretubazid, andrazide, niazid, piridizin, and many others. |
| Description | Isoniazid is an antibiotic that acts as a prodrug, being converted by bacterial catalase- |
| Chemical Properties | white crystalline powder |
| Originator | Nyrazid,Squibb,US,1952 |
| Uses | Isoniazid is an antimicrobial used for the prevention oftuberculosis infection or used concurrently with another agentfor the treatment of tuberculosis infection. Rifampin, pyrazinamide,or both of these agents are commonly used withisoniazid. Isoniazid is the only Food and Drug Administrationapproved drug to treat latent tuberculosis in order to prevent itfrom becoming active. |
| Uses | antibacterial, tuberculostatic |
| Uses | Antibiotic for treatment of Mycobacterium tuberculosis, inhibits mycolic acid biosynthesis. Metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. Selectively induces expression of CYP2E1. Reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 at clinically relevant concentrations. Antibacterial (tuberculostatic). |
| Uses | For the treatment of all forms of tuberculosis in which organisms are susceptible. |
| Definition | ChEBI: A carbohydrazide obtained by formal condensation between pyridine-4-carboxylic acid and hydrazine. |
| Indications | Isoniazid (isonicotinic acid hydrazide, or INH) is themost active drug for the treatment of tuberculosiscaused by susceptible strains. It is a synthetic agent witha structural similarity to that of pyridoxine. |
| Manufacturing Process | 4 parts of 4-cyanopyridine in 12 parts of water were reacted with 4 parts ofhydrazine hydrate in the presence of 0.08 part of sodium hydroxide at 100°Cunder reflux for 7 hours. The product, after filtration and evaporation todryness, was crystallized from ethanol. The yield of isonicotinyl hydrazideamounted to 3.27 parts which is 62% of the theoretical. |
| Brand name | Inh (Novartis); Nydrazid (Bristol-MyersSquibb); Nydrazid (Sandoz); Rimifon (Roche). |
| Therapeutic Function | Antitubercular |
| Biological Functions | Its action is bactericidal against replicating organisms, but it appears to be only bacteriostatic at best against semidormant and dormant populations. After treatment with INH, M . tuberculosis loses its acid fastness, which may be interpreted as indicating that the drug interferes with cell wall development. |
| Synthesis Reference(s) | The Journal of Organic Chemistry, 20, p. 412, 1955 DOI: 10.1021/jo01122a002 |
| Antimicrobial activity | Susceptibility to isoniazid is virtually restricted to the M. tuberculosiscomplex (MIC 0.01–0.2 mg/L). It is highly bactericidalagainst actively replicating M. tuberculosis. Other mycobacteriaare resistant, except for some strains of M. xenopi (MIC 0.2 mg/L)and a few strains of M. kansasii (MIC 1 mg/L). |
| Acquired resistance | Mutations in the katG gene, the inhA gene or its promoterregion, and in the intergenic region of the oxyR–ahpC locusconfer resistance to isoniazid. The relativeproportions of such mutations vary geographically andare related to the distribution of the various lineages or superfamiliesof M. tuberculosis. Isoniazid resistance is the commonest form of drug resistanceworldwide and the great majority of strains resistant toanother agent are also resistant to isoniazid. |
| General Description | Odorless colorless or white crystals or white crystalline powder. Taste is slightly sweet at first and then bitter. pH (1% aqueous solution) 5.5-6.5. pH (5% aqueous solution) 6-8. |
| Air & Water Reactions | Sensitive to air and light. Absorbs insignificant amounts of moisture at 77°F at relative humidities up to approximately 90%. Water soluble. Dust can be explosive when suspended in air at specific concentrations. |
| Reactivity Profile | Isoniazid is incompatible with chloral, aldehydes, iodine, hypochlorites and ferric salts. Isoniazid is also incompatible with oxidizers. Isoniazid may react with sugars and ketones. Isoniazid can react as a weak acid or a weak base. Isoniazid can be decomposed by oxidative and reductive reactions. |
| Fire Hazard | Isoniazid is combustible. |
| Pharmaceutical Applications | One of a number of nicotinamide analogs found to have antituberculosisactivity, following the observation that nicotinamideinhibited the replication of M. tuberculosis. It is solublein water. The dry powder is stable if protected from light. It isa prodrug requiring oxidative activation by KatG, a mycobacterialcatalase–peroxidase enzyme. |
| Biochem/physiol Actions | Antibiotic for treatment of Mycobacterium tuberculosis, inhibits mycolic acid biosynthesis. Metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. Selectively induces expression of CYP2E1. Reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 at clinically relevant concentrations. |
| Mechanism of action | Isoniazid is active against susceptible bacteria only whenthey are undergoing cell division. Susceptible bacteriamay continue to undergo one or two divisions beforemultiplication is arrested. Isoniazid can inhibit the synthesisof mycolic acids, which are essential components ofmycobacterial cell walls.The mycobacterial enzyme catalase–peroxidase KatG activates the administered isoniazidto its biologically active form.The target sites for theactivated isoniazid action are acyl carrier protein AcpMand Kas A, a β-ketoaceyl carrier protein synthetase thatblocks mycolic acid synthesis. Isoniazid exerts its lethaleffects at the target sites by forming covalent complexes. |
| Pharmacology | Isoniazid is water soluble and is well absorbed whenadministered either orally or parenterally. Oral absorptionis decreased by concurrent administration ofaluminum-containing antacids. Isoniazid does not bind to serum proteins; it diffusesreadily into all body fluids and cells, including thecaseous tuberculous lesions. The drug is detectable insignificant quantities in pleural and ascitic fluids, as wellas in saliva and skin. The concentrations in the centralnervous system (CNS) and cerebrospinal fluid are generallyabout 20% of plasma levels but may reach closeto 100% in the presence of meningeal inflammation. Isoniazid is acetylated to acetyl isoniazid by N-acetyltransferase,an enzyme in liver, bowel, and kidney.Individuals who are genetically rapid acetylators will havea higher ratio of acetyl isoniazid to isoniazid than will slowacetylators. Rapid acetylators were once thought to bemore prone to hepatotoxicity, but this is not proved. Theslow or rapid acetylation of isoniazid is rarely importantclinically, although slow inactivators tend to develop peripheralneuropathy more readily. Metabolites of isoniazidand small amounts of unaltered drug are excreted inthe urine within 24 hours of administration. |
| Pharmacokinetics | Oral absorption: >95% Cmax 300 mg oral: 3–5 mg/L after 1–2 h Plasma half-life: 0.5–1.5 h (rapid acetylators) :2–4 h (slow acetylators) Volume of distribution: 0.6–0.8 L/kg Plasma protein binding: Very low Absorption and distribution Isoniazid is almost completely absorbed from the gut and is well distributed. Absorption is impaired by aluminum hydroxide. Therapeutic concentrations are achieved in sputum and CSF. It crosses the placenta and is found in breast milk. Metabolism Isoniazid is extensively metabolized to a variety of pharmacologically inactive derivatives, predominantly by acetylation. As a result of genetic polymorphism, patients are divisible into rapid and slow acetylators. About 50% of Caucasians and Blacks, but 80–90% of Chinese and Japanese, are rapid acetylators. Acetylation status does not affect the efficacy of daily administered therapy. The rate of acetylation is reduced in chronic renal failure. Excretion Nearly all the dose is excreted in the urine within 24 h, as unchanged drug and metabolic products. |
| Clinical Use | Isonicotinic acid hydrazide, isonicotinyl hydrazide, or INH(Nydrazid) occurs as a nearly colorless crystalline solid thatis very soluble in water. It is prepared by reacting the methylester of isonicotinic acid with hydrazine. Isoniazid is a remarkably effective agent and continuesto be one of the primary drugs (along with rifampin, pyrazinamide,and ethambutol) for the treatment of tuberculosis.It is not, however, uniformly effective against all formsof the disease. The frequent emergence of strains of the tuberclebacillus resistant to isoniazid during therapy wasseen as the major shortcoming of the drug. This problemhas been largely, but not entirely, overcome with the use ofcombinations. The activity of isoniazid is manifested on the growing tuberclebacilli and not on resting forms. Its action, which isconsidered bactericidal, is to cause the bacilli to lose lipidcontent by a mechanism that has not been fully elucidated.The most generally accepted theory suggests that the principaleffect of isoniazid is to inhibit the synthesis of mycolicacids, high–molecular-weight, branched β-hydroxyfatty acids that constitute important components of the cellwalls of mycobacteria. |
| Clinical Use | Isoniazid is among the safest and most active mycobactericidalagents. It is considered the primary drug foruse in all therapeutic and prophylactic regimens for susceptibletuberculosis infections. It is also included in thefirst-line drug combinations for use in all types of tuberculousinfections. Isoniazid is preferred as a singleagent in the treatment of latent tuberculosis infectionsin high-risk persons having a positive tuberculin skin reactionwith no radiological or other clinical evidence oftuberculosis. Mycobacterium kansasii is usually susceptibleto isoniazid, and it is included in the standard multidrugtreatment regimen. |
| Clinical Use | Tuberculosis (intensive and continuation phases) Prevention of primary tuberculosis in close contacts and reactivationdisease in infected but healthy persons (monotherapy) |
| Side effects | The incidence and severity of adverse reactions to isoniazidare related to dosage and duration of therapy.Isoniazid-induced hepatitis and peripheral neuropathyare two major untoward effects. |
| Side effects | Toxic effects are unusual on recommended doses and aremore frequent in slow acetylators. Many side effects are neurological,including restlessness, insomnia, muscle twitchingand difficulty in starting micturition. More serious but lesscommon neurological side effects include peripheral neuropathy,optic neuritis, encephalopathy and a range of psychiatricdisorders, including anxiety, depression and paranoia. Neurotoxicity is usually preventable by giving pyridoxine(vitamin B6) 10 mg per day. Pyridoxine should be givento patients with liver disease, pregnant women, alcoholics,renal dialysis patients, HIV-positive patients, the malnourishedand the elderly. Encephalopathy, which has been reported inpatients on renal dialysis, may not be prevented by, or respondto, pyridoxine, but usually resolves on withdrawal of isoniazid. Isoniazid-related hepatitis occurs in about 1% of patientsreceiving standard short-course chemotherapy. The incidenceis unaffected by acetylator status. It is more common in thoseaged over 35 years and preventive isoniazid monotherapyshould be used with care in older people. Less common side effects include arthralgia, a ‘flu’-likesyndrome, hypersensitivity reactions with fever, rashes and,rarely, eosinophilia, sideroblastic anemia, pellagra (whichresponds to treatment with nicotinic acid) and hemolysis inpatients with glucose-6-phosphate dehydrogenase deficiency.It exacerbates acute porphyria and induces antinuclear antibodies,but overt systemic lupus erythematosus is rare. |
| Synthesis | Isoniazid, isonicotinic acid hydrazide (34.1.1), is synthesized by reacting ethylester of isonicotinic acid with hydrazine. |
| Veterinary Drugs and Treatments | Isoniazid (INH) is sometimes used for chemoprophylaxis in smallanimals in households having a human with tuberculosis. It potentiallycan be used in combination with other antimycobacterialdrugs to treat infections of M. bovis or M. tuberculosis in dogs orcats. But because of the public health risks, particularly in the face ofincreased populations of immunocompromised people, treatmentof mycobacterial (M. bovis, M. tuberculosis) infections in domesticor captive animals is controversial. In addition, INH has a narrowtherapeutic index and toxicity is a concern (see Adverse Effects). In humans, isoniazid (INH) is routinely used alone to treat latenttuberculosis infections (positive tuberculin skin test) and incombination with other antimycobacterial agents to treat activedisease. |
| Environmental Fate | Isoniazid is a colorless, odorless, white crystalline powder thatis slowly oxidized by exposure to air. It undergoes degradationupon prolonged exposure to light. Isoniazid has a solubility of1 g per 8 ml water, 1 g per 50 ml ethanol, and it is slightlysoluble in chloroform and very slightly soluble in ether. A 10%solution of isoniazid has a pH of 6.0–8.0. |
| Metabolism | Isoniazid is extensively metabolized to inactive metabolites. The major metabolite is N-acetylisoniazid. The enzyme responsible for acetylation, cytosolic N-acetyltransferase, is produced under genetic control in an inherited autosomal fashion. Individuals who possess high concentrations of the enzyme are referred to as rapid acetylators, whereas those with low concentrations are slow acetylators. This may result in a need to adjust the dosage for fast acetylators. The N-acetyltransferase is located primarily in the liver and small intestine. Other metabolites include isonicotinic acid, which is found in the urine as a glycine conjugate, and hydrazine. Isonicotinic acid also may result from hydrolysis of acetylisoniazid, but in this case, the second product of hydrolysis is acetylhydrazine. Acetylhydrazine is acetylated by N-acetyltransferase to the inactive diacetyl product. This reaction occurs more rapidly in rapid acetylators. The formation of acetylhydrazine is significant in that this compound has been associated with the hepatotoxicity, which may occur during INH therapy. |
| Purification Methods | Crystallise isoniazide from 95% EtOH and dry it in a vacuum. [Beilstein 22 III/IV 545, 22/2 V 219.] |
| Toxicity evaluation | Isoniazid causes toxicity by altering the metabolism of pyridoxineand creating a functional deficiency. Pyridoxine isneeded for transamination, transketolization, decarboxylation,and biotransformation reactions. This occurs through three processes: (1) isoniazid metabolites form complexes with pyridoxineincreasing its urinary excretion with increasing doses; (2)isoniazid metabolites disrupt the conversion of pyridoxine to itsactive form, pyridoxine-50-phosphokinase; and (3) metabolitesdirectly inactivate pyridoxal-50-phosphate. Isoniazid-induced seizures are thought to be caused by thedepletion of gamma-aminobutyric acid (GABA). GABA is theprimary inhibitory neurotransmitter in the central nervoussystem that requires the cofactor pyridoxal-50-phosphate for itssynthesis from glutamate. Prolonged seizures commonly resultin plasma lactic acid accumulation that can lead to an aniongap metabolic acidosis. Isoniazid may worsen the severity ofacidosis by inhibiting the production of nicotinamideadensosinedinucleotide (NAD), a cofactor necessary for theconversion of lactate to pyruvate. Long-term exposure toisoniazid therapy commonly causes peripheral neuropathy dueto pyridoxine deficiency, and may induce pellagra, a niacindeficiency disorder. Niacin requires the cofactor pyridoxal-50-phosphate for its production from tryptophan. The exact mechanism of isoniazid-induced hepatotoxicity isunknown. However, it is thought to involve an idiopathicautoimmune mechanism or result from direct hepatic injuryfrom isoniazid or its metabolites. The metabolite thought to beresponsible is acetyl hydrazine, produced from isoniazidhydrolysis via cytochrome P450 (CYP)2E1. Persons with theCYP2E1c1/c1 genotype may be more susceptible to hepatotoxicity.The role acetylator status plays in hepatotoxicitycontinues to be debated, but it is currently thought that slowacetylators are at greater risk. Other risk factors includeincreasing age, chronic isoniazid overdose, comorbid conditionssuch as malnutrition, pregnancy, diabetes, HIV, renaldysfunction, hepatic dysfunction, alcoholism, and concomitantuse of enzyme inducing drugs. Other enzymes inhibited by isoniazid include the cytochromeP450 mixed function oxidases, monoamine oxidase,glutamate decarboxylase, and histaminase. The consequencesof these extensive enzymatic disturbances are mood elevation,decreased central nervous system GABA levels, depressed catecholaminesynthesis, defects in glucose and fatty acid oxidation,and impaired metabolism of other drugs. Important druginteractions include those with carbamazepine, phenytoin,rifampin, theophylline, valproate, and warfarin. Isoniazid isalso a weak monoamine oxidase inhibitor, and serotoninsyndrome and tyramine reactions to foods causing flushing,tachycardia, and hypertension are reported. Isoniazid does cross the placenta and enters the fetalcompartment; however, it has been determined to not bea human teratogen in studies. In acute toxicity, fetal deformitieshave been reported. |
| Precautions | High isoniazid plasma levels inhibit phenytoin metabolismand potentiate phenytoin toxicity when the twodrugs are coadministered. The serum concentrations ofphenytoin should be monitored, and the dose should beadjusted if necessary. |
| References | [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 10, p. 1260 - 1274 [2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1532 - 1537 [3] Patent: US2015/210679, 2015, A1. Location in patent: Paragraph 0091 [4] Patent: US2016/214969, 2016, A1. Location in patent: Paragraph 0076-0077 [5] Patent: CN105481765, 2016, A. Location in patent: Paragraph 0030; 0031; 0032 |
Isoniazid Preparation Products And Raw materials
| Raw materials | Potassium permanganate-->4-Methylpyridine-->Isonicotinic acid-->Hydrazine hydrate-->4-Cyanopyridine-->N-BUTYL ISONICOTINATE-->Isonicotinamide-->Methyl isonicotinate-->3,5-bis(pyridin-4-yl)-4-amino-1,2,4-triazole-->HYDRAZINE |
| Preparation Products | 4-ISOCYANATOPYRIDINE-->4-Pyridylcarbinol-->Isonicotinic acid chloride-->Ethyl isonicotinate-->4,4'-(1H-1,2,4-Triazole-3,5-diyl)dipyridine-->1,2-Bis(4-pyridylcarbonyl)hydrazine-->4-METHYL-5-PYRIDIN-4-YL-4H-[1,2,4]TRIAZOLE-3-THIOL-->Pasiniazid-->N-(3-chlorophenyl)-2-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamide |
