Ketorolac tromethamine

Bezeichnung:Ketorolac tromethamine

CAS-Nr74103-07-4

Englisch Name:Ketorolac tromethamine

CBNumberCB2427540

SummenformelC19H24N2O6

Molgewicht376.41

MOL-Datei74103-07-4.mol

Ketorolac tromethamine physikalisch-chemischer Eigenschaften

Schmelzpunkt	160-161 C
storage temp.	2-8°C
Löslichkeit	H₂O: 15 mg/mL stable at least one month at −20 °C., soluble
Aggregatzustand	crystalline
Farbe	White to Light yellow
maximale Wellenlänge (λmax)	322nm(MeOH)(lit.)
Merck	14,5306
Stabilität	Hygroscopic
InChIKey	BWHLPLXXIDYSNW-UHFFFAOYSA-N
CAS Datenbank	74103-07-4(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	T
R-Sätze:	25-36/37/38-23/24/25
S-Sätze:	26-45-36/37/39
RIDADR	UN 2811 6.1/PG 3
WGK Germany	3
RTECS-Nr.	UY7759900
HazardClass	6.1(a)
PackingGroup	II
HS Code	2933995500

Gefahreninformationscode (GHS)

Ketorolac tromethamine Chemische Eigenschaften,Einsatz,Produktion Methoden

R-Sätze Betriebsanweisung:
R25:Giftig beim Verschlucken.
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
R23/24/25:Giftig beim Einatmen, Verschlucken und Berührung mit der Haut.
S-Sätze Betriebsanweisung:
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
Beschreibung
Ketorolac tromethamine is a nonsteroidal antiinflammatory agent that exhibits analgesic and antipyretic activity. The compound is effective in the management of moderate to severe postoperative pain. It is, however, the first of this type of agent to be administered parenterally as an analgesic and is specifically indicated for intramuscular injection. Ketorolac represents a useful alternative to the narcotic analgesics due to its lack of abuse potential.
Beschreibung
Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) and a non-selective COX inhibitor (IC₅₀ = 20 nM for both COX-1 and COX-2). It prevents increases in paw swelling, increases paw withdrawal latency in a hot-plate test, and decreases prostaglandin E₂ (PGE₂) levels in paw tissue in a mouse model of carrageenan-induced inflammation when administered at a dose of 30 mg/kg. Ketorolac is a racemic mixture containing the active (S)-ketorolac and inactive (R)-ketorolac enantiomers. Formulations containing ketorolac have been used to manage postoperative pain and as ophthalmic solutions to treat ocular pain and inflammation.
Chemische Eigenschaften
Off-White to Pale Yellow Solid
Chemische Eigenschaften
A carboxylic acid derivative nonsteroidal antiinflammatory agent, ketorolac tromethamine occurs as an off-white crystalline powder with a pKa of 3.54 (in water). More than 500 mg are soluble in one mL of water at room temperature. The commercially available injection is a clear, slightly yellow solution with a pH of 6.9 – 7.9. Sodium chloride is added to make the solution isotonic. Ketorolac tromethamine may also be known as RS-37619-00- 31-3; many trade names are available.
Originator
Syntex (USA)
Verwenden
Ketorolac is used primarily for its analgesic effects for short-term treatment of mild to moderate pain in dogs and rodents. The duration of analgesic effect in dogs is about 8 – 12 hours, but because of the availability of approved, safer NSAIDs for dogs, its use is questionable.
Verwenden
Analgesic;Cyclooxygenase Inhibitor
Verwenden
Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.
Definition
ChEBI: An organoammonium salt resulting from the mixture of equimolar amounts of ketorolac and tromethamine (tris). It has potent non-sedating analgesic and moderate anti-inflammatory effects. It is used in the short-term management of post-operative pain, and in eye drops to relieve the ocular itching associated with seasonal allergic conjunctivitis.
Indications
Ketorolac tromethamine is a pyrrolol-pyrrole nonsteroidal anti- inflammatory agent that inhibits prostaglandin formation. Prostaglandins mediate inflammation within the eye by disrupting the blood-aqueous barrier, inducing vasodilation and increasing intraocular pressure. Prostaglandins may also cause iris sphincter constriction (miosis) independent of cholinergic mechanisms. Ketorolac tromethamine is marketed for use before cataract extraction in human patients (to prevent miosis during surgery) and for control of post surgical inflammation, especially following cataract surgery. It is also approved for management of conjunctivitis associated with seasonal allergy in people. In veterinary medicine, ketorolac tromethamine is primarily used to control surgical or nonsurgical uveitis particularly in cases with concurrent corneal bacterial infection or ulceration when topical corticosteroids are contraindicated. It is also used in diabetic patients, especially smaller patients, adversely affected by systemic uptake of topically applied corticosteroids. Nonsteroidal agents like ketorolac tromethamine can be combined with topical steroids in patients with severe uveal inflammation.
Manufacturing Process
Preparation of 2-bromo-4-chloro-N-methyl-N-phenylbutanamide
4-Chlorobutanoyl chloride (62 g, 440 mmol) and phosphorus tribromide (3 g) were added to a distillation flask, and heated to 90°C. Bromine (77.5 g, 485 mmol) was added over eight hours, with the solution being allowed to decolorize between additions. After the addition was complete, and the solution decolorized, a vacuum was slowly applied, and the acid gases and phosphorus tribromide scrubbed. Unreacted starting material was distilled at 98-100°C/22 mm Hg, and the temperature slowly increased to 105°C, where a mixture of 2-bromo-4-chlorobutanoyl chloride and 2-bromo-4- chlorobutanoyl bromide began to distill. Pure 2-bromo-4-chlorobutanoyl bromide distilled at approximately 108°C. The combined yield of 2-bromo-4- chlorobutanoyl chloride and 2-bromo-4-chlorobutanoyl bromide was 100.5 g, with a bromide/chloride ratio of approximately 6:1. The mixture of 2-bromo- 4-chlorobutanoyl bromide and chloride is directly usable in the preparation of the butanamide, if desired, or may be separated and either component used.
2-Bromo-4-chlorobutanoyl bromide (300 mmol) was added to a solution of Nmethylaniline (320 mmol) and triethylamine (330 mmol) in toluene (340 mL). The reaction was exothermic, and the mixture was cooled to maintain the temperature at about 40°C. After the addition was complete, the resulting mixture was stirred for 30 minutes, 150 mL water was added, and the mixture was stirred further. The aqueous and organic phases were separated, and the organic phase was washed with 5% hydrochloric acid and with water. The toluene was evaporated completely under vacuum to yield 86.3 g 2-bromo-4- chloro-N-methyl-N-phenylbutanamide (98% yield, approximately 95-96% pure).
A solution of methylmagnesium chloride in butyl diglyme (4.0 L, 2.8 M, 11.2 mol, 2.8 equivalents with respect to 2-bromo-4-chloro-N-methyl-Nphenylbutanamide) was added to a 12 L 4-necked round bottom flask fitted with a mechanical stirrer and two 1 L addition funnels, under a nitrogen atmosphere. 2-Bromo-4-chloro-N-methyl-N-phenyl-butanamide (3.98 mol) was added to the first addition flask, and pyrrole (3.04 equivalents with respect to 2-bromo-4-chloro-N-methyl-N-phenyl-butanamide) was added to the second. The pyrrole was slowly added to the methylmagnesium chloride/butyl diglyme solution at 45-50°C over 3 hours. The resulting viscous mixture was cooled to 25°C and stirred for 30 min. 2-Bromo-4-chloro-Nmethyl-N-phenylbutanamide was added to the resulting mixture over a period of 2 hours at 25-30°C, and the resulting solution was stirred for another 3 hours.
The dark colored reaction mixture was transferred into 5.76 mol 2 N hydrochloric acid with rapid stirring for 1 hour. The aqueous phase was removed, and 0.8 L 15 weight % ammonium chloride in water was added to the organic phase. The resulting mixture was stirred at 35-40°C for 10 min, the aqueous phase then removed, and hexanes (2.4 L) added. The resulting suspension was cooled to -20°C and maintained at that temperature for a few minutes. The precipitate was filtered in a 300 mL sintered glass funnel and washed with hexanes (1 L). Drying of the solid under vacuum at 25-30°C yielded 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide (81% yield).
A solution of 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide in toluene was added dropwise at 85°C over 40 min to 1 hour to a stirred suspension of ALIQUAT 336 (phase transfer catalyst, 2 mol % with respect to pyrrolylbutanamide) and granular sodium hydroxide (3 equivalents) in toluene (50 mL). After the addition was complete, the suspension was stirred under a nitrogen atmosphere at a temperature of 85°C for 30 min, then cooled to 35°C. Cooled water (200 mL) was rapidly added to the mixture and stirred for 15 min at 25°C. The solution was rinsed with water and the layers were separated. The organic layer was washed with water, then distilled under atmospheric pressure to recover the t
Trademarks
Acular (Allergan); Toradol (Roche);Toradol IM.
Therapeutic Function
Analgesic, Antiinflammatory
Allgemeine Beschreibung
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards. Ketorolac Tromethamine belongs to the class of non-steroidal anti-inflammatory drugs, and its mode of action involves the inhibition of the bodily synthesis of prostagladins. It exhibits anti-inflammatory, antipyretic and analgesic effects.
Biochem/physiol Actions
Ketorolac is a non-steroidal agent that possesses moderate anti-inflammatory activity and is also a potent analgesic. It shows superior analgesic efficacy to that of the opioid analgesics like morphine in patients with moderate to severe postsurgical pain. It inhibits prostaglandin synthesis and platelet aggregation induced by arachidonic acid and collagen. It is a dual COX-1/COX-2 inhibitor.
Pharmakokinetik
After oral administration, ketorolac is rapidly absorbed; in dogs peak levels occur in about 50 minutes and oral bioavailability is about 50 – 75%.
Ketorolac is distributed marginally through the body. It does not appear to cross the blood-brain barrier and is highly bound to plasma proteins (99%). The volume of distribution in dogs is reported to be about 0.33 – 0.42 L/kg (similar in humans). The drug does cross the placenta.
Ketorolac is primarily metabolized via glucuronidation and hydroxylation. Both unchanged drug and metabolites are excreted mainly in the urine. Patients with diminished renal function will have longer elimination times than normal. In normal dogs, the elimination half-life is between 4 – 8 hours.
Pharmakologie
Like other NSAIDs, ketorolac exhibits analgesic, antiinflammatory, and antipyretic activity probably through its inhibition of cyclooxygenase with resultant impediment of prostaglandin synthesis. Ketorolac may exhibit a more potent analgesic effect than some other NSAIDs. It inhibits both COX-1 and COX-2 receptors.
Nebenwirkungen
The manufacturer indicates that ketorolac tromethamine does not enhance the spread of preexisting corneal fungal, viral or bacterial infections in animal models. Ketorolac tromethamine does not in and of itself induce postoperative pressure elevation other then that which frequently follows cataract extraction in people and animals.
Sicherheitsprofil
Ketorolac does cross the placenta. In humans, the FDA categorizes this drug as category C for use during the first two trimesters of pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In humans, all NSAIDs are assigned to category D for use during pregnancy during the third trimester or near delivery (There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.) Most NSAIDs are excreted in milk. Ketorolac was detected in human breast milk at a maximum milk:plasma ratio of 0.037. It is unlikely to pose great risk to nursing offspring.
Veterinary Drugs and Treatments
Ketorolac is used primarily for its analgesic effects for short-term treatment of mild to moderate pain in dogs and rodents. The duration of analgesic effect in dogs is about 8 – 12 hours, but because of the availability of approved, safer NSAIDs for dogs, its use is questionable.
Überdosierung
Limited information is available. The oral LD50 is 200 mg/kg in mice. GI effects, including GI ulceration are likely in overdoses in small animals. Metabolic acidosis was reported in one human patient. Consider GI emptying in large overdoses; patients should be monitored for GI bleeding. Treat ulcers with sucralfate; consider giving misoprostol early.
Vorsichtsmaßnahmen
Ketorolac is relatively contraindicated in patients with a history of, or preexisting, hematologic, renal or hepatic disease. It is contraindicated in patients with active GI ulcers or with a history of hypersensitivity to the drug. It should be used cautiously in patients with a history of GI ulcers, or heart failure (may cause fluid retention), and in geriatric patients. Animals suffering from inflammation secondary to concomitant infection, should receive appropriate antimicrobial therapy. Because ketorolac has a tendency to cause gastric erosion and ulcers in dogs, long-term use (>3 days) is not recommended in this species.

Ketorolac tromethamine Upstream-Materialien And Downstream Produkte

Ketorolac tromethamine Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

74103-07-4, Ketorolac tromethamine Verwandte Suche:

Send Inquriy