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Loperamide hydrochloride

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Loperamide hydrochloride Basic information
Loperamide hydrochloride Chemical Properties
  • Melting point:223-225°C
  • Density 1.1905 (rough estimate)
  • refractive index 1.6100 (estimate)
  • storage temp. Store at RT
  • solubility Slightly soluble in water, freely soluble in ethanol (96 per cent) and in methanol.
  • pka8.66(at 25℃)
  • form neat
  • Merck 14,5571
  • CAS DataBase Reference34552-83-5(CAS DataBase Reference)
Safety Information
  • Hazard Codes T
  • Risk Statements 25
  • Safety Statements 45
  • RIDADR UN 2811 6.1/PG 3
  • WGK Germany 3
  • RTECS TM4960000
  • HazardClass 6.1(b)
  • PackingGroup III
  • HS Code 29333990
  • ToxicityLD50 in mice (mg/kg): 75 s.c.; 28 i.p.; 105 orally; in rats (mg/kg): 185 orally (Niemegeers)
MSDS
Loperamide hydrochloride Usage And Synthesis
  • Chemical PropertiesWhite Solid
  • OriginatorImodium,Janssen,UK,1975
  • UsesLabeled Loperamide, which is used as an antidiarrheal
  • UsesCa channel blocker
  • UsesLoperamide hydrochloride is a Ca2+ channel protein inhibitor and MOR activator.
  • IndicationsLoperamide hydrochloride (Imodium) structurally resembles both haloperidol and meperidine. In equal doses, loperamide protects against diarrhea longer than does diphenoxylate. It reduces the daily fecal volume and decreases intestinal fluid and electrolyte loss. Loperamide produces rapid and sustained inhibition of the peristaltic reflex through depression of longitudinal and circular muscle activity.The drug also possesses antisecretory activity, presumably through an effect on intestinal opioid receptors.
  • DefinitionChEBI: A hydrochloride obtained by combining loperamide with one equivalent of hydrochloric acid. Used for treatment of diarrhoea resulting from gastroenteritis or inflammatory bowel disease.
  • Manufacturing Process23.6 parts of 2-oxo-3,3-diphenyl-tetrahydrofuranare melted at 100°C in an oil-bath and gaseous hydrogen bromide is introduced into it during 3 hours. The reaction mixture is cooled and triturated in benzene. The product is filtered off, washed with petroleum ether and dried in an exsiccator, yielding 4-bromo-2,2-diphenylbutyric acid; MP 127.5%.
    To a stirred suspension of 16 parts of 4-bromo-2,2-diphenylbutyric acid in 150 parts of chloroform are added dropwise 16 parts of thionyl chloride and the whole is stirred and refluxed for 2 hours. The reaction mixture is evaporated,yielding 4-bromo-2,2-diphenyl-butyrylchloride as a residue.
    60 parts of 4-bromo-2,2-diphenylbutyrylchloride are dissolved in 400 parts of toluene and gaseous dimethylamine is introduced slowly into the solution while cooling (temperature is kept at about 0°C). The introduction is ceased when dimethylamine escapes from the cooler, and stirring is continued for 2 hours at ordinary temperature. The precipitated product is filtered off and dissolved in a minimum quantity of water. The product is extracted with chloroform. The extract is dried and evaporated. The residue solidifies on triturating in 4-methyl-2-pentanone. The solid is filtered off and dried, yielding dimethyl -(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide; MP 169° to 171.5°C.
    A mixture of 6.33 parts of 4-(p-chlorophenyl)-4-piperidinol, 8 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2- pentanone is distilled azeotropically. Then there are added 12.12 parts of dimethyl-(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (from the preceding step) and the whole is stirred and refluxed for about 15 hours. The reaction mixture is filtered hot and the filtrate is evaporated.
    The oily residue is dissolved in 2-propanol and to this solution is added an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The whole is evaporated and the oily residue is warmed in diluted hydrochloric acid solution. Upon the addition of toluene, the salt is precipitated. It is filtered off, boiled in acetone, and filtered off again after cooling, yielding 4- (p-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenylpiperidine-1-butyramide hydrochloride; MP 222.1°C.
  • brand nameImodium (Janssen); Imodium (McNeil).
  • Therapeutic FunctionAntidiarrheal
  • Biological ActivityHigh affinity μ -opioid receptor agonist with peripheral selectivity (K i values are 2, 48 and 1156 nM for μ -, δ - and κ -opioid receptors respectively). Antidiarrhoeal and antihyperalgesic agent. Also a Ca 2+ channel blocker; at low micromolar concentrations it blocks broad spectrum neuronal HVA Ca 2+ channels and at higher concentrations it reduces Ca 2+ flux through NMDA receptor operated channels.
  • Mechanism of actionLoperamide also is a potent inhibitor of intestinal CYP3A4, increasing the intestinal absorption of other CYP3A4 substrates. The clinically significant drug interactions of loperamide with coadministered CYP3A4 and CYP2C8 substrates or inhibitors would be limited, however, because of its two metabolic pathways.
  • PharmacokineticsLoperamide is marketed as capsules (2 mg) and liquid (1 mg/5 mL) preparations. The recommended dose is 4 mg initially and an additional 2 mg following each diarrheal stool. The dose should not exceed 16 mg/day. It is too lipophilic to dissolve in water for an intravenous dosage form, a property that limits its abuse potential. The compound is highly lipophilic and undergoes slow dissolution, thus limiting the bioavailability of the agent to approximately 40% of the dose. Its low oral bioavailability also can be attributed to first-pass metabolism by both CYP2C8 and CYP3A4 to its primary N-demethyl metabolite. Peak plasma levels are reached in approximately 5 hours, with an elimination half-life of approximately 11 hours. Approximately 1% of the dose is excreted into the urine unchanged.
  • Clinical UseLoperamide is effective against a wide range of secretory stimuli and can be used in the control and symptomatic relief of acute diarrhea that is not secondary to bacterial infection.
  • Side effectsAdverse effects associated with its use include abdominal pain and distention, constipation, dry mouth, hypersensitivity, and nausea and vomiting.
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