What Is Clozapine?
Clozapine is a light yellow crystalline powder; it is odorless and tasteless. Soluble in chloroform, soluble in ethanol, almost insoluble in water. Also known as 8-chloro-11 (4-methyl-1-piperazinyl) -5H-dibenzo [B, E] [1,4] diazapyrene, density: 1.31 g / cm3 melting point: 182- 185 ° C, molecular formula: C18H19ClN4, has a good effect on the positive or negative symptoms of schizophrenia.
- Chinese name
- Clozapine
- Foreign name
- Clozapine
- Molecular formula
- C18H19CLN4
- Molecular weight
- 326.83
- CAS number
- 5786-21-0
- Clozapine is a light yellow crystalline powder; it is odorless and tasteless. Soluble in chloroform, soluble in ethanol, almost insoluble in water. Also known as 8-chloro-11 (4-methyl-1-piperazinyl) -5H-dibenzo [B, E] [1,4] diazapyrene, density: 1.31 g / cm3 melting point: 182- 185 ° C, molecular formula: C18H19ClN4, has a good effect on the positive or negative symptoms of schizophrenia.
Clozapine compounds
Clozapine Basic Information
- Chinese name: Clozapine
- Chinese alias: 8-chloro-11 (4-methyl-1-piperazinyl) -5H-dibenzo [B, E] [1,4] diazepine; 8-chloro-11- (4- (Methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazapine; clozapine; methanol test standard (clozapine, 1.0 MG / ML); chlorine Tazapine Impurities; Clozapine-D4; Mixtures for Clozapine Resolution
- English name: clozapine
- English alias: Iprox; Clozapin; Leponex; Fazaclo; Clorazil; CLOZARIL; Clozapine; Lepotex; Clozapinum; 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazepine;
- CAS number: 5786-21-0
- Molecular formula: C18H19ClN4
- Structural formula:
- Molecular weight: 326.82300
- Exact mass: 326.13000
- PSA: 30.87000
- LogP: 3.17210 [1]
Clozapine physical and chemical properties
- Appearance and properties: a yellow, crystalline powder, slightly soluble in water
- Density: 1.31 g / cm 3
- Melting point: 182-185 ° C
- Boiling point: 477.8ºC at 760 mmHg
- Flash point: 242.8ºC
- Refractive index: 1.681
- Stability: Stable at normal temperatures and pressures
- Storage conditions: Keep tightly closed. [1]
Clozapine Safety Information
- Symbol: GHS06 GHS08
- Signal Word: Danger
- Hazard statement: H301; H341; H361
- Cautionary statement: P281; P301 + P310
- Packing level: III
- Hazard category: 6.1 (b)
- Customs code: 2933990090
- Dangerous Goods Transport Code: UN 2811 6.1 / PG 3
- WGK Germany: 3
- Danger category code: R22; R36 / 37/38
- Safety instructions: S26
- RTECS number: HP1750000
- Dangerous goods mark: Xi [1]
Clozapine safety term
- S26In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
- After accidental contact with eyes, rinse immediately with plenty of water and seek medical advice.
Clozapine risk terminology
- R22Harmful if swallowed.
- Harmful if swallowed.
- R36 / 37 / 38Irritating to eyes, respiratory system and skin.
- Irritation of eyes, respiratory system and skin.
Clozapine Pharmacopoeia Standard
Clozapine main active ingredient
- This product is 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diaza. Calculated on dry basis, containing C18H19ClN4 shall not be less than 98.5%. [2]
Clozapine traits
- This product is light yellow crystalline powder; odorless and tasteless.
- This product is easily soluble in chloroform, soluble in ethanol, and almost insoluble in water. [2]
Clozapine melting point
- The melting point of this product (Appendix VIC of Part Two of the 2010 Pharmacopoeia) is 181 to 185 ° C. [2]
Clozapine absorption coefficient
- Take this product, weigh it accurately, add 0.5mol / L sulfuric acid solution-ethanol (1:99), dissolve and quantitatively dilute it to make a solution containing about 10g per 1ml, according to the UV-visible spectrophotometry method (2010 Pharmacopoeia Part II Appendix IVA), the absorbance is measured at the wavelengths of 242nm and 296nm, and the absorption coefficients are 710-770 and 293-320, respectively. [2]
Clozapine identification
- (1) Take about 100mg of this product, add equal amount of sodium carbonate and stir well. Place in a dry test tube and burn. Violet blue.
- (2) The infrared light absorption spectrum of this product should be consistent with the control spectrum ("Infrared Spectra of Drugs" 504).
- (3) Take the appropriate amount of this product and the clozapine reference substance, dissolve them in the appropriate amount of methanol, and dilute with mobile phase to make a solution containing 50 g per 1 ml as the test solution and reference solution solution. The chromatographic condition test, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution. [2]
Clozapine check
- relative substance
- Take about 25mg of this product, put it in a 50ml measuring flask, add 10ml of methanol, sonicate for 5 minutes to dissolve, dilute to the mark with mobile phase, shake well; take 5ml precisely, place in a 25ml measuring bottle, and dilute to the mark with mobile phase , Shake well, as the test solution; take an appropriate amount of precision, dilute with mobile phase to make a solution containing about 0.3g per 1ml, as a control solution. Tested according to high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 edition), using octadecylsilane bonded silica as a filler and methanol-0.4% triethylamine solution (70:30) as the mobile phase; detection wavelength It is 257nm. Take 20 l of the control solution and inject it into the liquid chromatograph, and adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 25% of the full scale. Then, 20 l of each of the test solution and the control solution was precisely measured and injected into the liquid chromatograph, and the chromatogram was recorded to 2.5 times the peak retention time of the main component. If there are impurity peaks in the chromatogram of the test solution, the area of a single impurity peak must not be greater than the area of the main peak of the control solution (0.3%), and the sum of the areas of the impurity peaks must not be more than twice the area of the main peak of the control solution (0.6%). [2]
- Loss on drying
- Take this product and dry it at 105 to constant weight, and the weight loss shall not exceed 1.0% (Appendix L of Part Two of the Pharmacopoeia of 2010 Edition). [2]
- 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%. [2]
- 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. [2]
Determination of clozapine
- Take about 0.1g of this product, accurately weigh, add 50ml of anhydrous glacial acetic acid to dissolve, according to the potentiometric titration method (2010 edition Pharmacopoeia Part II Appendix A), titrate with perchloric acid titration solution (0.1mol / L), and The results of the titrations are corrected with a blank test. Each 1ml of perchloric acid titration solution (0.1mol / L) is equivalent to 16.34mg of C18H19ClN4. [2]
Clozapine pharmacological action
- This strain is a dibenzodiazepine. Blocks serotonin (5-HT2A) and dopamine (DA1) receptors in the brain, blocks dopamine (DA4) receptors, and blocks dopamine (DA2) receptors Weak effect, in addition to anti-choline (M1), anti-histamine (H1) and anti-adrenergic receptor effect, extrapyramidal response and tardive dyskinesia are mild, generally do not cause prolactin in the blood Increase. It can directly inhibit the ascending activation system of the brain stem reticular structure, has a strong sedative and hypnotic effect, and is used to treat many types of schizophrenia. [3]
- Clozapine has a strong antipsychotic effect, but the extrapyramidal response is mild, indicating that the antipsychotic effect and the extrapyramidal response can be separated. Enlightened by clozapine, olanzapine and risperidone were successively discovered. [4]
Clozapine pharmacokinetics
- Oral absorption is fast and complete, and food has no effect on its absorption rate and extent. It is quickly and widely distributed to various tissues after absorption. Individual differences in bioavailability are large, about 50% to 60% on average, and have a first-pass effect in the liver. Peak plasma concentration was reached 3.2 hours (1 to 4 hours) after taking the drug, the elimination half-life (t1 / 2) averaged 9 hours (3.6 to 14.3 hours), apparent volume of distribution (Vd) 4.04 to 13.78 L / kg, and high tissue binding rate . Metabolized by the liver, 80% appear in the form of metabolites in urine and feces. The main metabolites are N-desmethylclozapine, N-oxide of clozapine, etc. At the same dose and a certain weight, the serum drug concentration of female patients is significantly higher than that of male patients. Smoking can accelerate the metabolism of this product, and renal clearance and metabolism are significantly reduced in the elderly. This product can be secreted from milk and can pass the blood-brain barrier. [3]
Clozapine indications
- This product is not only effective for positive symptoms of psychosis, but also effective for negative symptoms. It is applicable to all subtypes of acute and chronic schizophrenia, and has good effects on hallucinations and adolescents. It can also reduce the emotional symptoms associated with schizophrenia (eg depression, guilt, anxiety). For some patients who are ineffective or ineffective with traditional antipsychotic drugs, switching to this product may be effective. This product is also used in the treatment of mania or other psychotic disorders of agitation and hallucinations. Because it causes granulocytopenia, it is generally not suitable as the first choice. [3]
Clozapine usage and dosage
- Oral administration starts with a small dose, the first dose is 25 mg (1 tablet) once, 2 to 3 times a day, and gradually increases to the commonly used treatment amount of 200 to 400 mg (8 to 16 tablets) a day, and the high amount can reach 600 mg (24 tablets) a day. sheet). The maintenance amount is 100 ~ 200mg (4 ~ 8 tablets) per day. [3]
Clozapine Contraindications
- Severe heart, liver, kidney disease, coma, delirium, hypotension, epilepsy, glaucoma, bone marrow suppression or leukopenia are contraindicated. Those who are allergic to this product are prohibited. [3]
Clozapine adverse reactions
- 1. Strong sedative effect and more anticholinergic adverse reactions, such as dizziness, weakness, lethargy, sweating, salivation, nausea, vomiting, dry mouth, constipation, orthostatic hypotension, and tachycardia.
- 2, common appetite increase and weight gain.
- 3. Can cause abnormal changes in ECG. Can cause EEG changes or seizures.
- 4, can also cause increased blood sugar.
- 5. Serious adverse reactions are agranulocytosis and secondary infection.
- 6, can cause urinary incontinence or central system disorders, should be used with caution or not clinically. [3]
Clozapine precautions
- 1. Allergic rash and malignant syndrome should be discontinued immediately and treated accordingly.
- 2. Those with central nervous system depression should be used with caution. Use with caution in patients with urinary retention.
- 3. During the first 3 months of treatment, the white blood cell count and classification should be checked every 1 to 2 weeks, and then check regularly.
- 4. Regularly check liver function and electrocardiogram.
- 5. Regularly check blood sugar to avoid diabetes or ketoacidosis.
- 6. It is not advisable to drive vehicles, operate machinery or operate at high altitude during medication.
- 7. Fever with unknown cause during medication should be suspended. [3]
Clozapine medication for pregnant and lactating women:
- Disable pregnant women. Breastfeeding women should stop breastfeeding while using this product. [3]
Clozapine for children:
- Not suitable for children under 12 years. [3]
Clozapine medication for elderly patients:
- Use with caution or use low doses. [3]
Clozapine Drug Action
- 1. Combining this product with ethanol or other central nervous system inhibitors can increase central inhibitory effect.
- 2. The combination of this product with antihypertensive drugs may increase the risk of orthostatic hypotension.
- 3. The combination of this product and anticholinergic drugs can increase the anticholinergic effect.
- 4. This product can be used in combination with digoxin, heparin, phenytoin, and warfarin to increase bone marrow suppression.
- 5. The combination of this product with lithium carbonate may increase the risk of convulsions, malignant syndrome, insanity and dystonia.
- 6. This product combined with fluvoxamine, fluoxetine, paroxetine, sertraline and other antidepressants can increase the levels of plasma clozapine and norclazapine.
- 7. The combination of this product with macrolide antibiotics can significantly increase the plasma clozapine concentration and has been reported to induce seizures. [3]
Clozapine rescue measures
- Symptoms of overdose poisoning: The most common symptoms and include delirium, coma, tachycardia, hypotension, respiratory depression or failure, excessive salivation, etc. Epilepsy has also been reported.
- Treatment: Establish and maintain an open airway, prompt vomiting and gastric lavage, and provide symptomatic treatment and supportive therapy according to the condition.
- The main symptoms of poisoning are respiratory depression (shallow, irregular breathing), decreased blood pressure and body temperature, cyanosis, diminished or disappeared spine reflexes, lethargy and even coma, and finally death due to respiratory paralysis. Time should be spent for early rescue:
- 1. Detoxification: (1) gastric lavage: those who are poisoned soon can use 1: 2000 1: 5000 potassium permanganate solution or 5% sodium bicarbonate, warm saline for gastric lavage. (2) Catheter: 40ml of 50% sodium sulfate. Because the absorption of trace Mg2 + can deepen the central inhibition, it is forbidden to use magnesium sulfate. (3) Diuretic: Intravenous injection of 10% GS accelerates urine, which can accelerate drug excretion; Intravenous injection of 50% GS or intravenous infusion of mannitol controls cerebral edema and accelerates drug excretion; long-acting or intermediate-effect drugs are weakly acidic, and can be calm when poisoned Drops of sodium bicarbonate or sodium lactate solution alkalize the urine, increase its water solubility, reduce renal tubular reabsorption and promote excretion.
- 2. Symptoms: (1) Respiratory depression: oxygen and artificial respiration. In severe cases, you can inject memantic sleep or return to Su Ling, but it should be used with caution and not excessive. (2) Low blood pressure: infusion or booster drugs such as neo-Fulin, Alamin. (3) Pay attention to heat preservation, strengthen nursing, and prevent infection with antibacterial drugs. [3]
Clozapine related substance toxicity report
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2. Biochemical toxicity-inhibit or induce other enzymes |
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2. Behavioral toxicity-convulsions or seizure thresholds affected 3. Lung, chest or respiratory toxicity-respiratory depression |
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2. Reproductive toxicity-other changes 3. Reproductive toxicity-reduced weight gain in newborns |
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- [5-32]