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| | Indometacin Chemical Properties |
| Melting point | 158-162 °C | | Boiling point | 499.4±45.0 °C(Predicted) | | density | 1.2135 (rough estimate) | | refractive index | 1.6800 (estimate) | | storage temp. | Store at RT | | solubility | ethanol: 50 mg/mL, clear, yellow-green | | form | White to off-white powder | | pka | 4.5(at 25℃) | | color | White to Light yellow to Light orange | | Water Solubility | Soluble in acetone (40 mg/mL - clear, yellow solution), ethanol (20 mg/mL), ether, castor oil; Soluble in chloroform (50 mg/mL - clear, yellow, extremely viscous solution); decomposed by strong alkali but stable in neutral or slightly acidic media; insoluble in water. | | Sensitive | Light Sensitive | | Merck | 14,4968 | | BRN | 497341 | | BCS Class | 2 | | Stability: | Stable. Incompatible with strong oxidizing agents. | | InChIKey | CGIGDMFJXJATDK-UHFFFAOYSA-N | | CAS DataBase Reference | 53-86-1(CAS DataBase Reference) | | NIST Chemistry Reference | Indomethacin(53-86-1) | | EPA Substance Registry System | Indomethacin (53-86-1) |
| | Indometacin Usage And Synthesis |
| anti-inflammatory analgesic | Indomethacin is a kind of stronger corticoid anti-inflammatory and antipyretic and analgesic, by inhibiting cyclooxygenase reducing the synthesis of prostaglandin (PG), to prevent the formation of the nere impulses, inflammation tissue inhibiting inflammatory reaction, including inhibition of leukocyte chemotaxis and lysosomal enzyme release, etc., and produce antipyretic, analgesic and anti-inflammatory effects. Indomethacin anti-inflammatory, antipyretic effect is very strong, its anti-inflammatory effect is better than bute, 84 times better than hydrocortisone, and sugar cortical hormone, used in combination with aspirin, bute, can reduce their dosage, toxic and side effects, improve curative effect; Second is antipyretic effect, 10 times than amidopyrine ;its analgesic action is weak , only to the inflammatory pain has obvious analgesic effect, but the effect is good for inflammatory pain than Baotai loose, analgin and salicylic acid. Clinical is mainly used for the salicylic acid, drugs are less tolerance or curative effect is not obvious in the acute and chronic rheumatic or rheumatoid arthritis, ankylosing spondylitis, slippery bursa phlogistic, tenosynovitis, articular capsulitis, osteoarthritis and acute gout and cancerous pain, etc.In recent years, the researchers try to use indomethacin biliary colic, dysmenorrhea, migraine, glomerulonephritis, polyuria, salmonella gastroenteritis, orthostatic hypotension, bart syndrome and so on, all have good curative effect.It can also be used to treat eye pigment meningitis, keratitis, scleritis, glaucoma and fever caused by cancer or other difficult to control the fever. Dermatologist for lupus erythematosus (sle), white plug syndrome, scleroderma, nodular erythema, herpes zoster, joint type of psoriasis, etc. photosensitive dermatitis induced by topical treatment of eczema, allergic dermatitis, and local pain. | | Pharmacokinetics | Oral medicine absorbed quickly and completely, can absorb more than 90% of the dosage of food with in 4 h, take medicine of acid containing aluminum and magnesium can be slightly slowed absorption, plasma protein conjugation rate is about 99%. After oral 25 mg, tmax is 1~4 h, the blood medicine peak concentration (Cmax) is 1.4 mu g/ml, when 50 mg, Cmax is 2.8 mu g/ml; Half-life (t1/2) of an average is 4.5 h, premature extended obviously. A small amount of indomethacin can through the blood-brain barrier. And through the placenta.This article in the liver metabolism go methyl chloride and chlorobenzene formyl chloride, and can be hydrolyzed into recycle indomethacin to absorb. Renal excretion from 60%, 10%~20% in prototype discharge; Part with droppings.33% from the bile excretion, 1.5% were prototype;In the breast milk also has a discharge (up to 0.5~2.0 mg daily).This product can not be dialysis to remove.
| | usage and dosage | 1.Anti-rheumatism: adult dosage: oral: early quantity from 25 to 50 mg each time, 2~4 times a day, immediately take at food service or after a meal. Such as good tolerance, the daily dosage can be increased from 25 to 50 mg per week, the most mount should not be more than 200 mg a day. Arthritis patients such as persistent pain at night or morning stiffness, can give quantity of 100 mg in bed all day.
2. Resistance to gout: oral: At the beginning quantity is 100 mg once, then 50 mg, three times a day, until the pain relief, and then gradually reduced as soon as possible, until the drug withdrawal.
3. Antifebrile: adult dosage: oral: 25~50 mg each time, 3~4 times daily.Rectal drug delivery: every time 50 mg, 50 to 100 mg per day. Pediatric dosage: oral: 0.5~1 mg/kg each time, 3 times a day.
The above information is Chemicalbook Hanya edited.
| | Side effects | Adverse reactions of Indomethacin are high incidence , common adverse reactions are as follows:
1. nausea, vomiting, abdominal pain, diarrhea, anorexia, serious ulcers can occur and cause bleeding and perforation. After dinner, that can reduce the incidence.
2. common headache, dizziness, fatigue, occasional seizures, mental derangement, syncope, etc. Should be paid attention to in due course.
3.the skin pruritus, erythema, urticaria, and one of the few of asthma, breathing problems and even breathing, circulation inhibition.
4.Inhibition of hematopoietic system such as granulocytopenia, aplastic anemia, thrombocytopenia, and so on. Although rare, but more severe consequences.There are also some other similar to aspirin reaction, notes are also the same.
| | matters need attention | 1.indomethacin and aspirin have cross allergic. Caused by aspirin allergic asthmatic patients, the application of this product can be induced bronchospasm. Other non steroidal anti-inflammatory drugs to which are allergic may also be allergic to this product.
2.This product is contraindicated with active ulcer disease, ulcerative colitis and history, epilepsy, Parkinson's disease, mental disease, liver and kidney function, the goods or aspirin or other nonsteroidal anti-inflammatory drug allergic person, angioedema or bronchial asthma. This product for the last 3 months of pregnancy can make fetal ductus arteriosus closure and result in persistent pulmonary hypertension, so pregnant women, disabled. This product can be discharged from the milk, breast-feeding women also disable.
3.This product is used for patients with cardiac insufficiency, and hypertension (because this product sodium can lead to water retention, hemophilia and other patients with hemorrhagic disease (because this product can make the bleeding time prolonged, aggravate bleeding tendency), aplastic anemia, granulocytopenia disease patients (this product is inhibition of hematopoietic system).Age < 14 years old children should not be commonly used drug, When it is applied，it should be closely observed.Easily occur in elderly patients with renal toxicity, which should also be careful.
4.Because indomethacin has inhibition to the platelet aggregation, which can make the bleeding time prolonged, the role after the drug was stopped sustainable. During the blood urea nitrogen and serum creatinine，levels are also often higher. During the medication，it should be regularly check routine blood and liver and kidney function. Case reports referred to in this article that the product can lead to corneal composure and retinal change (including macular degeneration), if it comes to the blurred vision eye exams should be done immediately.
5.Drug overdose (especially when dose > 150 mg a day) is easy to cause toxic reactions such as nausea, vomiting, tension headaches, sleepiness, spirit, behavior disorders, etc., with vomiting or gastric lavage, symptomatic and supportive treatment.
| | chemical property | White or slightly yellow crystalline powder. Melting point is 158-162℃, soluble in acetone, slightly soluble in ethanol, chloroform, ether, almost insoluble in water.
| | Uses | 1.The product is anti-inflammatory, and antipyretic effect is obvious, mainly is used for salicylates to tolerance or the effect is not significant rheumatism and arthritis, ankylosing light spondylitis, osteoarthritis.
2.Non steroid anti-inflammatory analgesic
| | Used in Particular Diseases | Acute Gouty Arthritis:
Dosage and Frequency: 25–50 mg four times a day for 3 days, then taper to twice daily for 4–7 days
| | methods of production | Para aminophenylmethylether is through diazotization, reduction, cyclization, hydrolysis, acidification to get indomethacin.
| | Category | Poisonous
| | classification of toxicity | Highly toxic.
| | acute toxicity | Oral administration: LD50 2.42 mg/kg in rats; oral administration of 11.84 mg/kg of LD50: in mice.
| | Combustible hazard characteristics | Open flame fuel; high heat decomposition of toxic chloride and nitrogen oxide gas.
| | Storage and transportation characteristics | Low temperature and dry air ventilation; and oxidant, food additives separately.
| | Extinguisher | Foam, fog water, sand, carbon dioxide.
| | Description | Aqueous solutions of indomethacin are not stable because of the ease of hydrolysis of the p-chlorobenzoyl group.
The original synthesis of indomethacin by Shen et al. involved the formation of 2-methyl-5-methoxyindole acetic
acid and subsequent
acylation after protection of the carboxyl group as the t-butyl ester. It was introduced in the United States in 1965. It
is still one of the most potent NSAIDs in use. It also is a more potent antipyretic than either aspirin or
acetaminophen, and it possesses approximately 10 times the analgetic potency of aspirin. | | Chemical Properties | Crystalline Solid | | Originator | Indocin,MSD,US,1965 | | Uses | Indomethacin is used in rheumatoid arthritis, nonspecific infectious polyarthritis, gouty
arthritis, osteoarthritis, ankylosing spondylitis, arthrosis, back pain, neuralgia, myalgia,
and other diseases accompanied by inflammation. | | Uses | Inhibits cyclooxygenase (IC50=0.1uM) selectively over liposygenases (IC50=100uM for 5-,12- and 15-LO). A clinically useful NAISD | | Uses | antiinflammatory, antipyretic, analgesic | | Indications | Indomethacin (Indocin) is used in the treatment of
acute gouty arthritis, rheumatoid arthritis, ankylosing
spondylitis, and osteoarthritis. It is not recommended
for use as a simple analgesic or antipyretic because of its
potential for toxicity.While indomethacin inhibits both
COX-1 and COX-2, it is moderately selective for COX-
1. It produces more CNS side effects than most of the
other NSAIDs. Severe headache occurs in 25 to 50% of
patients; vertigo, confusion, and psychological disturbances
occur with some regularity. GI symptoms also
are more frequent and severe than with most other NSAIDs. Hematopoietic side effects (e.g., leukopenia,
hemolytic anemia, aplastic anemia, purpura, thrombocytopenia,
and agranulocytosis) also may occur. Ocular
effects (blurred vision, corneal deposits) have been observed
in patients receiving indomethacin, and regular
ophthalmological examinations are necessary when the
drug is used for long periods. Hepatitis, jaundice, pancreatitis,
and hypersensitivity reactions also have been
noted. | | Definition | The antiinflammatory drug indomethacin. | | Manufacturing Process | (A) 2-Methyl-5-Merhoxy-3-Indolylacetic Anhydride: Dicyclohexylcarbodiimide
(10 g, 0.049 mol) is dissolved in a solution of 2-methyl-5-methoxy-3-indolylacetic acid (22 g, 0.10 mol) in 200 ml of THF, and the solution is
allowed to stand at room temperature for 2 hours. The precipitated urea is
removed by filtration, and the filtrate is evaporated in vacuo to a residue and
flushed with Skellysolve 6. The residual oily anhydride is used without
purification in the next step.
(B) t-Butyl 2-Methyl-5-Merhoxy-3-Indolylacetate: t-Butyl alcohol (25 ml) and
fused zinc chloride (0.3 g) are added to the anhydride from Part A. The
solution is refluxed for 16 hours and excess alcohol is removed in vacuo. The
residue is dissolved in ether, washed several times with saturated bicarbonate,
water, and saturated salt solution. After drying over magnesium sulfate, the
solution is treated with charcoal, evaporated, and flushed several times with
Skellysolve B for complete removal of alcohol. The residual oily ester (18 g,
93%) is used without purification.
(C) t-Buryl 1-p-Chlorobenzoyl-2-Methyl-5-Mefhoxy-3-Indolylacetate: A stirred
solution of ester (18 g, 0.065 mol) in dry DMF (450 ml) is cooled to 4°C in an
ice bath, and sodium hydride (4.9 g, 0.098 mol, 50% susp.) is added in
portions. After 15 minutes, p-chlorobenzoyl chloride (15 g, 0.085 mol) is
added dropwise during 10 minutes, and the mixture is stirred for 9 hours
without replenishing the ice bath. The mixture is then poured into one liter of
5% acetic acid, extracted with a mixture of ether and benzene, washed
thoroughly with water, bicarbonate, saturated salt, dried over magnesium
sulfate, treated with charcoal, and evaporated to a residue which partly
crystallizes. This is shaken with ether, filtered and the filtrate is evaporated to
a residue (17 g) which solidifies after being refrigerated overnight.
The crude product is boiled with 300 ml of Skellysolve 6, cooled to room
temperature, decanted from some gummy material, treated with charcoal,
concentrated to 100 ml, and allowed to crystallize. The product thus obtained
(10 g) is recrystallized from 50 ml of methanol and gives 4.5 g of analytically
pure material, MP 103° to 104°C.
(D) 1 -p-Chlorobenzoyl-2-Methyl-5-Methoxy-3-Indolylacetic Acid: A mixture of
1 g ester and 0.1 g powdered porous plate is heated in an oil bath at 210°C
with magnetic stirring under a blanket of nitrogen for about 2 hours. No
intensification of color (pale yellow) occurs during this period. After cooling
under nitrogen, the product is dissolved in benzene and ether, filtered, and
extracted with bicarbonate. The aqueous solution is filtered with suction to
remove ether, neutralized with acetic acid, and then acidified weakly with
dilute hydrochloric acid. The crude product (0.4 g, 47%) is recrystallized from
aqueous ethanol and dried in vacuo at 65°C: MP 151°C. | | Brand name | Indocin (Merck);Argan. | | Therapeutic Function | Antiinflammatory | | World Health Organization (WHO) | Indometacin was introduced in 1963 and it is one of the first
NSAIDs. Convulsions are rarely reported in relation with the use of this group of
agents. Indometacin farnesil is a pro-drug of indometacin, and the occurrence of
gastro-intestinal adverse effects could be expected. See also under nonsteroidal
antiinflammatory agents. | | Biological Functions | Indomethacin (Indocin) is an acetic acid derivative related
functionally to sulindac (Clinoril), a prodrug with
a long half-life, and etodolac (Lodine).They are metabolized
in the liver and excreted as metabolites in the bile and via the kidney. They are potent inhibitors of
COX and thus extremely effective antiinflammatory
agents. | | General Description | From the time of its introduction in 1965, indomethacin(Indocin) has been widely used as an analgesic to relieve inflammatorypain associated with RA, OA and ankylosingspondylitis, and, to a lesser extent, in gout. Although both itsanalgesic and anti-inflammatory activities are well established,its use is often limited because of frequent GI distressand potential drug interactions, especially with warfarinfurosemide, and lithium (i.e., it elevates blood levels oflithium as a result of reducing renal blood flow and thereforeincreases lithium toxicities).
Following oral administration, indomethacin is rapidlyabsorbed and is 90% protein bound at therapeutic plasmaconcentrations. The drug has a biological half-life ofabout 5 to 10 hours and a plasma clearance of 1 to 2.5 ml/kgper minute. It is metabolized to its inactive, O-desmethyl,N-deschlorobenzoyl-, and O-desmethyl, N-deschlorobenzoylindomethacinmetabolites. | | General Description | Crystals. | | Air & Water Reactions | Practically insoluble in water. Decomposes in alkali. | | Reactivity Profile | A weak organic acid. | | Fire Hazard | Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. | | Pharmaceutical Applications | Indomethacin is a nonsteroidal anti-inflammatory agent used in pain and moderate to severe
inflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase)
inhibitor and therefore interrupts the production of prostaglandins.
A series of new silicon compounds, based on the structure of indomethacin, have been synthesised and
are under investigation as novel anticancer agents. The carboxyl group of indomethacin was reacted with
a series of amino-functionalised silanes. The resulting products have been shown to be significantly more
lipophilic and more selective to COX-2. Furthermore, in vitro testing has shown an increased uptake of the
new compounds at the tumour site. The silane-functionalised indomethacin derivatives exhibited a 15-fold
increased antiproliferative effect when tested against pancreatic cancer . | | Pharmaceutical Applications | Indomethacinis a nonsteroidal anti-inflammatory agent used in pain and moderate to severe
inflammation in rheumatic diseases and other musculoskeletal disorders. It is a COX (cyclooxygenase)
inhibitor and therefore interrupts the production of prostaglandins. | | Biological Activity | Cyclooxgenase (COX) inhibitor; displays selectivity for COX-1 (IC 50 values are 230 and 630 nM for human COX-1 and COX-2 respectively). Widely used anti-inflammatory agent. | | Biochem/physiol Actions | Cyclooxygenase (COX) inhibitor that is relatively selective for COX-1. | | Clinical Use | Indomethacin is available for the short-term treatment of acute gouty arthritis, acute pain of ankylosing spondylitis,
and osteoarthritis. An injectable form to be reconstituted also is available as the sodium trihydrate salt for IV use in
premature infants with patent ductus arteriosus. Because of its ability to suppress uterine activity by inhibiting
prostaglandin biosynthesis, indomethacin also has an unlabeled use to prevent premature labor. | | Side effects | All of these drugs produce analgesic effects, antipyresis,
and antiinflammatory effects.Due to the high incidence
of gastric irritation, headache, nausea, and other side effects,
including hematological effects and coronary
vasoconstriction, they are not useful as an initial treatment
for pain. GI irritation and ulceration occur to a
lesser extent with etodolac. Indomethacin is useful in
the treatment of acute gout, osteoarthritis, ankylosing
spondylitis, and acceleration of the closure of the ductus
arteriosus in premature infants. The tocolytic effects of
indomethacin to prevent preterm labor are the result of
its effects on prostaglandin synthesis. However, the toxicity
of the drug limits such application, since it increases
fetal morbidity. Indomethacin is contraindicated
in pregnancy, in asthmatics, and in those with gastric ulcers
or other ulceration of the GI tract. Indomethacin
may increase the symptoms associated with depression
or other psychiatric disturbances and those associated
with epilepsy and Parkinson’s disease. The drug should
be used with caution in such patients. | | Synthesis | Indomethacin, 1-(n-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetic acid
(3.2.51), has been synthesized by various methods. All of the proposed methods of synthesis start with 4-methoxyphenylhydrazine. According to the first method, a reaction is done to
make indole from phenylhydrazone (3.2.46) by Fischer?ˉs method, using levulinic acid
methyl ester as a carbonyl component, hydrogen chloride as a catalyst, and ethanol as a solvent, to give the methyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.47). This
product is hydrolyzed by an alkali into 5-methoxy-2-methyl-3-indolylacetic acid (3.2.48),
from which tert-butyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.49) is formed
by using tert-butyl alcohol and zinc chloride in the presence of dicyclohexylcarbodiimide.
The resulting product undergoes acylation at the indole nitrogen atom by p-chorobenzoyl
chloride in dimethylformamide, using sodium hydride as a base. The resulting tert-butyl
ester of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid (3.2.50), further
undergoes thermal decomposition to the desired acid, indomethacin (3.2.51) [111,112]. 
| | Drug interactions | Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists:
antagonism of hypotensive effect; increased risk of
nephrotoxicity and hyperkalaemia.
Analgesics: avoid concomitant use of 2 or more
NSAIDs, including aspirin (increased side effects);
avoid with ketorolac (increased risk of side effects
and haemorrhage).
Antibacterials: possibly increased risk of convulsions
with quinolones.
Anticoagulants: effects of coumarins and
phenindione enhanced; possibly increased risk of
bleeding with heparins, dabigatran and edoxaban -
avoid long term use with edoxaban.
Antidepressants: increased risk of bleeding with
SSRIs and venlaflaxine.
Antidiabetic agents: effects of sulphonylureas
enhanced.
Antiepileptics: effects of phenytoin enhanced.
Antipsychotics: possible severe drowsiness with
haloperidol.
Antivirals: increased risk of haematological toxicity
with zidovudine; concentration possibly increased by
ritonavir.
Ciclosporin: increased risk of nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate.
Diuretics: increased risk of nephrotoxicity,
hyperkalaemia with potassium-sparing diuretics;
antagonism of diuretic effect
.
Lithium: lithium excretion reduced.
Pentoxifylline: possibly increased risk of bleeding.
Probenecid: excretion of indometacin reduced.
Tacrolimus: increased risk of nephrotoxicity. | | Metabolism | Indometacin is metabolised in the liver primarily by
demethylation and deacetylation; it also undergoes
glucuronidation and enterohepatic circulation.
Indometacin is mainly excreted in the urine,
approximately 60%, the pH of the urine can affect this
amount. Lesser amounts are excreted in the faeces. | | storage | Room temperature |
| | Indometacin Preparation Products And Raw materials |
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