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.

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 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

Toxicity data from literature and journals
Numbering
Toxicity type
testing method
Test object
Dosage used
Toxic effect
1
Acute toxicity
oral
Adult woman
168 mg / kg / 4W-I
1. Hematological toxicity-agranulocytosis 2. Nutrition and metabolic system toxicity-elevated body temperature
2
Acute toxicity
oral
Adult woman
104 mg / kg / 26D-I
1. Hematological toxicity-eosinophilia
3
Acute toxicity
oral
Adult male
3280 mg / kg / 82W-I
1. Hematological toxicity-agranulocytosis
4
Acute toxicity
oral
child
4762 ug / kg
1. Behavioral toxicity-ataxia 2. Behavioral toxicity-muscle contraction or spasm 3. Behavioral toxicity-mental depression
5
Acute toxicity
oral
Adult male
5357 ug / kg / 5D-I
1. Behavioral toxicity-hallucinations and perceptual distortions 2. Behavioral toxicity-mental depression 3. Cardiotoxicity-increased heart rate and no decrease in blood pressure
6
Acute toxicity
oral
Adult male
429 mg / kg / 60D-I
1. Behavioral toxicity-muscle contraction or spasm
7
Acute toxicity
oral
Adult woman
20 mg / kg
1. Behavioral toxicity-coma 2. Gastrointestinal toxicity-Changes in the structure and function of the pancreas 3. Hematological toxicity-Leukopenia
8
Acute toxicity
oral
Adult woman
280 mg / kg / 5W-I
1. Hepatotoxicity-Hepatitis (hepatocyte necrosis), spread 2. Hematological toxicity-Eosinophilia
9
Acute toxicity
oral
Adult male
27 mg / kg / 13D-I
1. Autonomic neurotoxicity-smooth muscle relaxation 2. Behavioral toxicity-hallucinations and perceptual distortions 3. Behavioral toxicity-ataxia
10
Acute toxicity
oral
Humanity
5 mg / kg / 7D-I
1. Cardiotoxicity-increased heart rate and no decrease in blood pressure
11
Acute toxicity
oral
Adult male
4286 ug / kg / 11D-I
1. Gastrointestinal toxicity-excessive exercise, diarrhea 2. Hematological toxicity-changes in blood cell counts 3. Nutrition and metabolic system toxicity-elevated body temperature
12
Acute toxicity
oral
Adult woman
28 mg / kg / 2W-I
1. Gastrointestinal toxicity-changes in structure and function of the pancreas
13
Acute toxicity
oral
Adult male
2211 mg / kg / 37W-I
1. Hematological toxicity-changes in serum composition (such as TP, bilirubin, cholesterol)
2. Biochemical toxicity-inhibit or induce other enzymes
14
Acute toxicity
oral
Adult male
270 mg / kg / 6W-I
1. Lung, chest or respiratory toxicity-changes in the structure and function of the trachea and bronchi 2. Gastrointestinal toxicity-excessive exercise, diarrhea 3. Hematological toxicity-agranulocytosis
15
Acute toxicity
oral
Adult male
86 mg / kg / 15D-I
1. Cardiotoxicity-increased heart rate and no decrease in blood pressure 2. Lung, chest or respiratory toxicity-other changes 3. Nutritional and metabolic system toxicity-increased body temperature
16
Acute toxicity
oral
Adult male
429 mg / kg
1. Behavioral toxicity-muscle contraction or spasm 2. Behavioral toxicity-coma 3. Cardiotoxicity-increased heart rate and no decrease in blood pressure
17
Acute toxicity
oral
Adult woman
96 mg / kg / 48D-I
1. Hematological toxicity-leukopenia 2. Hematological toxicity-agranulocytosis
18
Acute toxicity
oral
Adult male
40 mg / kg
1. Behavioral toxicity-coma 2. Vascular toxicity-decreased blood pressure regulation 3. Lung, chest or respiratory toxicity-respiratory depression
19
Acute toxicity
oral
Rat
251 mg / kg
Detailed effects are not reported other than lethal dose
20
Acute toxicity
Subcutaneous injection
Rat
240 mg / kg
1. Behavioral toxicity-changes in sleep time (including changes in righting reflex)
2. Behavioral toxicity-convulsions or seizure thresholds affected 3. Lung, chest or respiratory toxicity-respiratory depression
twenty one
Acute toxicity
Intravenous injection
Rat
41600 ug / kg
1. Behavioral toxicity-convulsions or seizure thresholds affected 2. Behavioral toxicity-ataxia 3. Lung, chest or respiratory toxicity-respiratory depression
twenty two
Acute toxicity
Intramuscular injection
Rat
210 mg / kg
Detailed effects are not reported other than lethal dose
twenty three
Acute toxicity
oral
Mouse
150 mg / kg
1. Nutrition and metabolic system toxicity-decreased body temperature
twenty four
Acute toxicity
Intraperitoneal injection
Mouse
90 mg / kg
1. Behavioral toxicity-convulsions or seizure thresholds are affected 2. Behavioral toxicity-muscle contractions or spasms 3. Lung, chest or respiratory toxicity-dyspnea
25
Acute toxicity
Subcutaneous injection
Mouse
194 mg / kg
1. Behavioral toxicity-lethargy 2. Behavioral toxicity-affected by convulsions or seizure thresholds 3. Behavioral toxicity-excitement
26
Acute toxicity
Intravenous injection
Mouse
36500 ug / kg
1. Behavioral toxicity-lethargy 2. Behavioral toxicity-convulsions or seizure thresholds affected 3. Lung, chest or respiratory toxicity-respiratory depression
27
Acute toxicity
oral
dog
145 mg / kg
1. Gastrointestinal toxicity-nausea, vomiting
28
Acute toxicity
oral
Guinea Pig
510 mg / kg
Detailed effects are not reported other than lethal dose
29
Chronic toxicity
oral
Rat
900 mg / kg / 30D-I
1. Liver toxicity-changes in liver weight 2. Nutrition and metabolic system toxicity-weight loss or rate of weight loss
30
Chronic toxicity
oral
Rat
3650 mg / kg / 1Y-I
1. Behavioral toxicity-lethargy 2. Hepatotoxicity-other changes 3. Nutritional and metabolic system toxicity-weight loss or rate of weight loss
31
Chronic toxicity
Intraperitoneal injection
Rat
504 mg / kg / 21D-I
1. Behavioral toxicity-autism 2. Nutrition and metabolic system toxicity-decreased body temperature
32
Chronic toxicity
oral
dog
6320 mg / kg / 52W-I
1. Eye toxicity-tearing 2. Behavioral toxicity-lethargy 3. Gastrointestinal toxicity-changes in the structure or function of salivary glands
33
Chronic toxicity
oral
monkey
14560 mg / kg / 2Y-I
1. Eye toxicity-drooping of the eyelid 2. Behavioral toxicity-lethargy 3. Cardiotoxicity-other changes
34
Mutation toxicity
oral
Drosophila
2 mg / 2D
35
Mutation toxicity
Human lymphocyte
10 mg / L
36
Reproductive toxicity
oral
Rat
1080 mg / kg, 16-22 days after female conception
1. Reproductive toxicity-affect the vitality index of the newborn (such as alive on the 4th day of birth)
2. Reproductive toxicity-other changes 3. Reproductive toxicity-reduced weight gain in newborns
37
Reproductive toxicity
oral
Rat
24 mg / kg, 9-14 days after conception
1. Reproductive toxicity-increased mortality before embryo implantation 2. Reproductive toxicity-abnormal development of the musculoskeletal system 3. Reproductive toxicity-other changes
38
Reproductive toxicity
oral
Rat
96 mg / kg, 9-14 days after conception
1. Reproductive toxicity-affecting the live birth index of newborns
39
Reproductive toxicity
oral
Mouse
48 mg / kg, 7-12 days after conception
1. Reproductive toxicity-fetal toxicity (such as fetal dysplasia but not death)
[5-32]

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