What Is Moclobemide?
The chemical name of morphobexamide is 4-chloro-N- [2- (4-morpholinylethyl)] benzamide, which is white or off-white crystal or crystalline powder; odorless and slightly bitter. Soluble in methanol, ethanol or chloroform, soluble in acetone, slightly soluble in water, soluble in glacial acetic acid. Clinically, it is a monoamine oxidase inhibitor type antidepressant. Its role is to reversibly inhibit the A-type monoamine oxidase in the brain, thereby increasing the levels of norepinephrine, dopamine and serotonin in the brain. It plays an antidepressant effect and has a rapid effect. , The characteristics of rapid recovery of monoamine oxidase activity after drug withdrawal.
- Chinese name
- Moclobemide
- Foreign name
- moclobemide
- CAS number
- 71320-77-9
- Molecular formula
- C13H17ClN2O2
- Mild nausea, dry mouth, headache, dizziness, sweating, palpitations, insomnia, orthostatic hypotension, etc.
- Rare side effects are allergic rash.
- Occasional disturbances of consciousness, elevated blood pressure, and impaired liver function.
- Epilepsy may be induced at high doses. [5]
- Patients with severe liver and kidney dysfunction should be used with caution.
- This product is forbidden to be used with other antidepressants at the same time to avoid the risk of causing high serotonin syndrome.
- This product is contraindicated in patients using central analgesics (peperidine, codeine, methadine), ephedrine, pseudoephedrine, or phenylpropanolamine.
- Patients should be discontinued immediately when they have a tendency to turn to manic episodes.
- It is not advisable to drive vehicles, operate machinery or work at height during medication.
- Blood medication and heart, liver, and kidney function should be checked regularly during medication.
- Switch to other antidepressants, and it is recommended to start using this product after 2 weeks of discontinuation; fluoxetine should be discontinued for 5 weeks before starting to use this product.
- Use with caution in pregnant women. Breastfeeding women should stop breastfeeding when using this product.
- Reduce the dosage of medication in elderly patients as appropriate. [5]
- Combined with cimetidine, it can delay the metabolism of this product.
- Combined with cyproheptadine, it can prolong and strengthen the anticholinergic effect.
- Combined with carbamazepine, it can cause acute hypertension, high fever and seizures.
- Combined with droperidol, it can increase cardiotoxicity.
- Combined with epinephrine 2 receptor agonists, it can cause palpitations, agitation, or mild mania.
- Combined with antidiabetic drugs, it may cause severe hypoglycemia and other reactions due to stimulation of insulin secretion. [5]
- Performance: After overdose, after about 12 hours of incubation period, the central nervous excitement quickly appears, showing agitation, sweating, tachycardia, myotonia, hyperreflexia, delirium, hypertension and high fever. When the body temperature is over 40 ° C and the diastolic blood pressure exceeds 120mmHg (16kPa), there may be signs of hypertensive encephalopathy such as severe headache, vomiting, optic papillary edema, and seizures. A few patients have a tendency to hypotension, respiratory depression and bleeding.
- Treatment: The following measures should be taken in time: timely gastric lavage to remove gastric toxins; infusion and forced diuresis with osmotic diuretics, urine acidification (can enter a large amount of vitamin C) is beneficial to accelerate the excretion of drugs; Symptomatic treatment and supportive therapy. [5]
- The chemical name of morphobexamide is 4-chloro-N- [2- (4-morpholinylethyl)] benzamide, which is white or off-white crystal or crystalline powder; odorless and slightly bitter. Soluble in methanol, ethanol or chloroform, soluble in acetone, slightly soluble in water, soluble in glacial acetic acid. Clinically, it is a monoamine oxidase inhibitor type antidepressant. Its role is to reversibly inhibit the A-type monoamine oxidase in the brain, thereby increasing the levels of norepinephrine, dopamine and serotonin in the brain. , The characteristics of rapid recovery of monoamine oxidase activity after drug withdrawal.
Introduction of Morclobemide Compounds
Morclobemide Basic Information
- Chinese name: Moclobemide;
- Chinese alias: 4-chloro-N-2- (4-morpholinyl) ethylbenzamide; Morclobemide, 4-chloro-N-2- (4-morpholinyl) ethylbutyramide ; Niclosamide; 4-chloro-N-2- (4-morpholinyl) ethylbutyramide; mecllobamine;
- English name: moclobemide
- English alias: Manefix; ro11-1163; Moclobemide; Moclamide; aurorix; Moclamine; Moclaime; MODOBEMDE; moclbemide; manerix;
- CAS number: 71320-77-9
- Molecular formula: C 13 H 17 ClN 2 O 2
- Structural formula:
- Molecular weight: 268.73900
- Exact mass: 268.09800
- PSA: 41.57000
- LogP: 1.73080
Physical and Chemical Properties of Morclobemide
- Appearance and properties: white to off-white solid
- Density: 1.206 g / cm 3
- Melting point: 137 ° C
- Boiling point: 447.7ºC at 760 mmHg
- Flash point: 224.6ºC
- Refractive index: 1.55
- Storage conditions: Room temp
Moclobemide Safety Information
- Packing level: III
- Hazard category: 6.1 (b)
- Dangerous Goods Transport Code: 3249
- Danger category code: R22
- Safety instructions: S26-S39
- RTECS number: CV2462000
- Dangerous goods mark: Xn [1]
Morclobemide molecular structure data
- 1. Molar refractive index: 71.03
- 2. Molar volume (cm / mol): 222.8
- 3. Isotonic specific volume (90.2K): 571.8
- 4. Surface tension (dyne / cm): 43.3
- 5. Polarizability (10-24cm3): 28.16
Calculated Chemical Data for Morclobemide
- 1. Hydrophobic parameter calculation reference value (XlogP): 1.5
- 2.Number of hydrogen-bonded donors: 1
- 3.Number of hydrogen bond acceptors: 3
- 4.Number of rotatable chemical bonds: 4
- 5.Number of tautomers: 2
- 6. Topological molecular polar surface area 41.6
- 7.Number of heavy atoms: 18
- 8.Surface charge: 0
- 9.Complexity: 262
- 10.Number of isotope atoms: 0
- 11. Determine the number of atomic stereocenters: 0
- 12. Uncertain number of atomic stereocenters: 0
- 13. Determine the number of chemical bond stereocenters: 0
- 14. Uncertain number of chemical bond stereocenters: 0
- 15. Number of covalent bond units: 1 [2]
Morclobemide synthesis method
- Method 1: Bromoethylamine hydrobromide is dissolved in water and benzene, 5% sodium hydroxide is added dropwise, the aqueous layer is separated, pyridine is added, and p-chlorobenzoyl chloride is added dropwise at 25 ° C. After refluxing, it was allowed to cool, suction filtered, washed with water, dried, and recrystallized from benzene to obtain an amide product in a yield of 91.8%. The amide was stirred with morpholine and ethyl acetate, water was added, and the pH was adjusted to 1 or 2 with hydrochloric acid. The ester layer was separated and extracted twice with ethyl acetate. The aqueous layer was neutralized with 10% sodium hydroxide to a Ph value of 8-9. The solid was collected by filtration, and recrystallized from isopropanol to obtain white needle-shaped crystals of moclobemide, with a yield of 80.2%, and a melting point of 136 to 137 ° C. The total yield can reach 73.6%.
You can also operate as follows. Bromoethylamine hydrobromide is dissolved in water, and p-chlorobenzoyl chloride and sodium hydroxide solution are added dropwise at 0 ~ 5 ° C under vigorous stirring. After the addition was continued, the amide product was obtained in a yield of 98.7%. The amide and morpholine can be stirred and refluxed to obtain moclobemide simply. The crude product is recrystallized from isopropanol with a yield of 75.3% and a melting point of 136 to 137 ° C. The total yield can reach 74.3%.
- Method 2: Acrylamide is dissolved in water, and an addition reaction with morpholine is performed at a low temperature. The resulting morpholinylpropionamide solution is directly treated with Hofmann degradation by adding an alkaline solution of sodium hypochlorite without any treatment. After the treatment, morpholinylethylamine can be obtained. nD1.4739.
- P-chlorobenzoic acid and ethyl chloroformate in acetone solution in the presence of triethylamine react to form ethyl p-chlorobenzoyloxyformate. The mixed acid anhydride has strong reactivity, and the morpholine ethyl obtained above Molebexamide was obtained by amine reaction with a yield of 58.9% and a melting point of 136 to 137 ° C. Although the reaction step of this method is relatively long, the raw materials used are relatively simple.
- 2. Preparation of N- (2-hydroxyethyl) -p-chlorobenzamide
- Add 125 g (0.8 mol) of p-chlorobenzoic acid, 300 ml of methanol and 48.5 g (0.16 mol) of concentrated H2SO to the reaction flask, and stir under reflux for 4 h. Evaporate the methanol under reduced pressure, add ice water, stir, filter, and wash the filter cake with cold water. Pump to dryness to obtain a white solid. Add this solid to the reaction flask, add 76ml (1.3mol) of ethanolamine and an appropriate amount of ammonium chloride, stir and reflux for 3h. Cool, pour into ice water, filter, and filter cake with 5% sodium hydroxide aqueous solution Washed, washed with absolute ethanol, dried, and dried to obtain 129.6g of white crystal N- (2-hydroxyethyl) -chlorobenzamide, yield 78.1%, mp110 ~ 115ºC.
- 3. Preparation of N- (2-chloroethyl) -p-chlorobenzamide
- Add 85 g (0.43 mol) of N- (2-hydroxyethyl) p-chlorobenzamide and 250 ml of dichloromethane to the reaction bottle. Slowly add 93 ml (1.28 mol) of thionyl chloride at room temperature with stirring. The internal temperature of the process is not more than 25ºC. After dripping, stir the reaction at 40 ~ 50ºC for 1h. After the reaction is complete, evaporate the solvent and excess SOCl2 under reduced pressure. Add ice water to the residue, stir, filter, and wash the filter cake to neutrality. , Dried and recrystallized from toluene to obtain 83.2 g of N- (2-chloroethyl) -p-chlorobenzamide as white crystals, yield 89.8%, mp 104 ~ 106ºC.
- 4. Synthesis of Morclobemide
- Add 54.5 g (0.5 mol) of N- (2-chloroethyl) p-chlorobenzamide, 43.5 g (0.5 mol) of morpholine, 26.5 g (0.25 mol) of anhydrous Na2CO3 and 250 ml of toluene into the reaction flask. Stir to reflux 5h. Cool, filter, wash the cake with water to neutrality, recrystallize with 50% isopropanol aqueous solution, filter, and dry to obtain white crystals 40.7 g of moclobemide, yield 60.7%, mp136 ~ 139ºC. Content 99.0% (HPLC normalization method). [2]
Moclobemide uses
- Selective reversible inhibitor of monoamine oxidase A, with less side effects and good tolerance, can be used by young and old. This is a new generation of antidepressants that can also treat children with ADHD.
- This product is a new generation of monoamine oxidase inhibitors, which is different from traditional monoamine oxidase inhibitors in that it has selective inhibition of monoamine oxidase A and is reversible, and it is not necessary to fasting casein-containing foods during medication. This product is used for depression. It is effective in treating bipolar and unipolar mental illness, endogenous, functional, reactive, and symptomatic depression, and is especially suitable for elderly patients. [2]
Morclobemide Pharmacopoeia Standard
Source (name) and content (potency) of Morclobemide
- This product is 4-chloro-N- [2- (4-morpholinylethyl)] benzamide. Calculated on dry basis, containing C13H17ClN2O2 shall not be less than 99.0%.
Morclobemide traits
- This product is white or off-white crystal or crystalline powder; odorless, slightly bitter.
- This product is easily soluble in methanol, ethanol or chloroform, soluble in acetone, slightly soluble in water, and easily soluble in glacial acetic acid.
- Melting point
- The melting point of this product (Appendix VIC in Part Two of the 2010 Pharmacopoeia) is 136 to 140 ° C.
- Absorption coefficient
- Take this product, weigh it accurately, add 0.1mol / L hydrochloric acid solution to dissolve and quantitatively dilute it to make a solution containing about 10g per 1ml, according to the UV-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part II of the 2010 edition) at 240nm The absorbance was measured at the wavelength, and the absorption coefficient () was 557 to 591.
Morclobemide identification
- (1) Take about 10mg of this product, add 5ml of dilute hydrochloric acid and 20ml of water to dissolve, and take 2 drops of 5ml of bismuth potassium iodide test solution to form an orange-red precipitate.
- (2) Take the solution under the absorption coefficient and measure it according to the UV-Vis spectrophotometry (Appendix IV A of Pharmacopoeia Part II of the 2010 edition). It has a maximum absorption at a wavelength of 240nm and a minimum absorption at a wavelength of 214nm.
- (3) The infrared light absorption spectrum of this product should be consistent with the control spectrum (Figure 740 of "Infrared Spectra of Drugs").
Morclobemide test
- Alkalinity
- Take 1.0g of this product, add 10ml of water, sonicate for 10 minutes, filter, and measure the filtrate according to law (Appendix VI H of the second edition of the Pharmacopoeia 2010), the pH value should be 7.3 ~ 8.5. Take 0.60g of chloride, add 50ml of water, shake for 5 minutes, filter, take 25ml of the filtrate, check according to law (Appendix A of Part II of the Pharmacopoeia of 2010 Edition), and compare with a control solution made of 6.0ml of standard sodium chloride solution Must not be thicker (0.020%).
- Sulfate
- Take 2.0g of this product, add 50ml of water, sonicate for 5 minutes, filter, take 25ml of filtrate, check according to law (Appendix B of Pharmacopoeia Part II of the 2010 edition), and compare it with a control solution made of 3.0ml of standard potassium sulfate solution. Thick (0.030%).
- relative substance
- Take this product, add the mobile phase to dissolve and make a solution containing 1.5mg per 1ml as the test solution; take an appropriate amount, add the mobile phase and dilute it to make a solution containing 15g per 1ml, as the control solution. According to the high performance liquid chromatography (2010 edition Pharmacopoeia Part II Appendix VD) test, cyanosilane bonded silica gel was used as the filler; 0.14% triethylamine solution (the pH value was adjusted to 6.0 with phosphoric acid solution (1 2)) Methanol (65:35) is the mobile phase; the detection wavelength is 235nm. The theoretical plate number is calculated to be not lower than 2000 based on the morphobex peak. Take 20l of the control solution and inject it into the liquid chromatograph to adjust the detection sensitivity to make the main component chromatographic The peak height is about 25% of the full scale; then, 20 l of each of the test solution and the control solution are accurately measured, injected into the liquid chromatograph, and the chromatogram is recorded to 2.5 times the peak retention time of the main component. If there are impurity peaks in the chromatogram, the area of a single impurity peak must not be greater than 0.5 times (0.5%) the area of the main peak of the control solution; the sum of the area of each impurity peak must not be greater than the area of the main peak of the control solution (1.0%).
- Loss on drying
- Take this product and dry it to constant weight at 105 ° C, and the weight loss shall not exceed 0.5% (Appendix L of Pharmacopoeia Part II of 2010 Edition).
- Residue on ignition
- Take 1.0g of this product and check it according to law (Appendix N of Part Two of the 2010 Pharmacopoeia). The residual residue shall not exceed 0.1%.
- Heavy metal
- Take the residue left under the item of burning residue and check it according to law (Appendix H of the second edition of the Pharmacopoeia of 2010 Edition, the second method H), the content of heavy metals must not exceed 20 parts per million.
- Arsenic salt
- Take 1.0g of this product, add 1g of calcium hydroxide, mix, add a small amount of water, stir well. After drying, burn with a small fire to charify, burn at 500-600 to completely ash, let cool, add 5ml of hydrochloric acid and 23ml of water was dissolved, and it was checked according to law (Appendix J First Law of Pharmacopoeia Part II of 2010 Edition), and it should meet the requirements (0.0002%).
Determination of Morclobemide
- Take about 0.2g of this product, accurately weigh, add 20ml of glacial acetic acid to dissolve, add 1 drop of crystal violet indicator solution, titrate with perchloric acid titration solution (0.1mol / L) until the solution becomes blue, and then titrate the result Calibration with blank test. Each 1ml of perchloric acid titration solution (0.1mol / L) is equivalent to 26.87mg of C13H17ClN2O2. [3]
Moclobemide Analysis Method
- Method name: Morclobemide API-Determination of Morclobemide-Non-aqueous titration method
- Scope of application: This method uses the titration method to determine the content of morphobexamide in morphobexamide drug substances.
- This method is applicable to morphobexamide APIs.
- Principle of the method: Add glacial acetic acid to the test sample, and after dissolving, add the crystal violet indicator solution, titrate the solution with blue perchloric acid until the solution turns blue, and correct the titration result with a blank test. Calculate according to the amount of titrant used Content of chlorbemide.
- Reagent: 1. Glacial acetic acid
- 2. Perchloric acid titrant (0.1mol / L)
- 3. Crystal violet indicator liquid
- 4. Reference potassium hydrogen phthalate
- equipment:
- Sample preparation: 1. Perchloric acid titration solution (0.1mol / L)
- Preparation: Take 750mL of anhydrous glacial acetic acid (calculated with water content, add 5.22mL of acetic anhydride per 1g of water), add 8.5mL of perchloric acid (70 ~ 72%), shake well, let cool, add an appropriate amount of anhydrous glacial acetic acid 1000mL, shake well and leave for 24 hours. If the test sample is easily acetylated, the water content of the solution must be determined by the moisture measurement method, and then the water content of the solution is adjusted to 0.01% ~ 0.2% with water and acetic anhydride.
- Calibration: Take about 0.16g of standard potassium hydrogen phthalate dried to constant weight at 105 , accurately weigh, add 20mL of anhydrous glacial acetic acid to dissolve, add 1 drop of crystal violet indicator solution, and slowly titrate with this solution to Blue, and the titration results are corrected with a blank test. Each 1mL of perchloric acid titration solution (0.1mol / L) is equivalent to 20.42mg of potassium hydrogen phthalate. Calculate the concentration of this solution based on the consumption of this solution and the amount of potassium hydrogen phthalate taken.
- Crystal violet indicator liquid
- Take 0.5 g of crystal violet and add 100 mL of glacial acetic acid to dissolve.
- Operation steps: Precisely weigh about 0.2g of the test sample, add 20mL of glacial acetic acid to dissolve, add 1 drop of crystal violet indicator solution, titrate with perchloric acid titrant (0.1mol / L) until the solution becomes blue, and titrate The results are corrected with a blank test. Each 1mL of perchloric acid titration solution (0.1mol / L) is equivalent to 26.87mg of C13H17ClN2O2.
- Note: "Precision weighing" means that the weighed weight should be accurate to one thousandth of the weighed weight. "Precision measurement" means that the accuracy of measuring the volume should meet the accuracy requirements of the volume pipette in national standards. [4]
Overview of Morclobemide
- Moclobemide, English name Moclobemide, chemical name p-chlorobenzamide, is a reversible inhibitor of selective monoamine oxidase-A developed by Roche in 1990. Mainly used for unipolar and bipolar endogenous depression, deep or chronic non-endogenous depression. It does not have early side effects of monoamine oxidase inhibitors (MAOI) such as isopropylhydrazine, phenelzine, etc. The side effects of "cheese", high blood pressure, and severe liver damage occur during use. The antidepressant feature of the drug is its ability to selectively treat monoamine oxidase A. Type has an inhibitory effect, can improve sleep quality, has no effect on alertness or short and long memory, and can reduce the effect on recognition function. It is effective in antidepressant and antihypoxia, especially suitable for elderly depression patients with heart and kidney disease. Its curative effect is exact, clinical safety is good, and the spectrum of action is wide, which is better than other antidepressants currently used in clinical practice. The product is now available in more than 50 countries. [5]
Pharmacological effects of Morclobemide
- This product is a monoamine oxidase inhibitor (MAOI). It reversibly inhibits type A monoamine oxidase (MAO-A) and improves the levels of norepinephrine (NA), dopamine (DA) and serotonin (5-HT) in the brain. Levels that produce antidepressant effects. Compared with irreversible MAOI, it has the characteristics of fast enzyme inhibition and rapid recovery of MAO activity after drug withdrawal. [5]
Morclobemide Pharmacokinetics
- Oral absorption is easy, single oral administration of 50 ~ 300mg, peak plasma concentration is 0.3 ~ 2.7g / ml, peak time is 1 ~ 2 hours. Bioavailability is positively correlated with dose and repeated use. The plasma protein binding rate is about 50%, and the apparent distribution volume is 75 ~ 95L / kg. It is widely distributed in the body, and is metabolized by the liver, t1 / 2 is 2 to 3 hours, and the average residence time of patients with liver cirrhosis is prolonged, so this type of patients needs to be reduced by half. Patients with moderate renal impairment generally do not need to make dose adjustments. This product can be secreted by milk. [6]
Indications for Morclobemide
- 1. For the treatment of endogenous depression, neurological depression and psychotic and reactive depression.
- 2. It is especially suitable for elderly depression and has no effect on psychomotor and recognition functions.
- 3. Effective for children with ADHD and social phobia. It also has a certain effect on sleep disorders. [7]
Contraindications to Morclobemide
- 1. Are you allergic to chlorbemamine, pregnant women and breastfeeding?
- 2. Patients with pheochromocytoma, severely impaired liver function, and manic depression are contraindicated. [7]
Dosage of Morclobemide
- 1. Generally 300mg per day, depending on the condition can be reduced to 150mg per day, can also be increased to 600mg, orally after meals.
- 2. The elderly and those with liver dysfunction do not need to adjust the dose; those with severe liver dysfunction should reduce the dose by 1/3 to 1/2. [7]
Morclobemide adverse reactions
Moclobemide precautions
Morclobemide interaction
Moclobemide overdose
Moclobemide quality checklist
- Xiaogan Shenyuan Chemical Co., Ltd.
- xiaogan shenyuan chempharm co.ltd
- Inspection report
- Certificate of Analysis
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