What Are the Most Common Clopidogrel Interactions?

Clopidogrel is used to prevent and treat heart, brain and other arterial circulation disorders caused by high platelet aggregation, such as recent stroke, myocardial infarction and diagnosed peripheral arterial disease.

Drug type: Essential medicines
Drug name: Clopidogrel

English name: Clopidogrel
Chinese alias: Clopidogrel

Clopidogrel Basic Information

Chinese name: Clopidogrel

Chinese alias: A- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothiophene 3,2-C-pyridine-5 (4H) methyl acetate hydrogen sulfate; clopidogrel ; Clopidogrel

English name: Clopidogrel

English alias: Clopidogrelum; Zyllt; methyl (2S) -2- (2-chlorophenyl) -2- (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetate;

Plavix

CAS number: 113665-84-2

Molecular formula: C ₁₆ H ₁₆ ClNO ₂ S

Molecular weight: 321.82200

Exact mass: 321.05900

PSA: 57.78000

LogP: 3.61180

Structural formula:

Clopidogrel physical and chemical properties

Density: 1.317g / cm ³

Boiling point: 423.7ºC at 760mmHg

Flash point: 210ºC

The disulfate is commonly used as a white powder, insoluble in water, but easily soluble in water with a pH of 1. Soluble in methanol.

Clopidogrel Safety Information

WGK Germany: 3

Danger category code: R22

Safety instructions: S26; S36

Dangerous goods sign: Xn

Clopidogrel production method

Racemic 2- (2-chlorophenyl) glycine (I) is esterified with methanol under the action of hydrogen chloride to obtain racemic 2- (2-chlorophenyl) glycine methyl ester (II). +)-Tartaric acid is resolved to obtain (+)-(II). Then alkylate with 2- (2-bromoethyl) thiophene in methyl acetate and dipotassium hydrogen phosphate; or with 2- [2- (phenylsulfonyloxy) ethyl] thiophene in methyl acetate In the presence of sodium bicarbonate, compound (III) is obtained by alkylation. Finally, it was cyclized with formic acid and formaldehyde to obtain clopidogrel ^[1] .

Clopidogrel Pharmacology

It is a platelet aggregation inhibitor that selectively inhibits the binding of ADP to platelet receptors and inhibits the activation of ADP-mediated glycoprotein GPIIb / IIIa complex, and inhibits platelet aggregation. Can also inhibit non-ADP-induced platelet aggregation. The effect on platelet ADP receptors is irreversible. Oral absorption is rapid, and the protein binding rate in plasma is 98%. It is metabolized in the liver, and the main metabolites have no anti-platelet aggregation effect.

Clopidogrel indication

It is used to prevent and treat heart, brain and other arterial circulation disorders caused by high platelet aggregation, such as recent stroke, myocardial infarction and diagnosed peripheral arterial disease.

Clopidogrel usage and dosage

Due to different dosage forms and specifications, please read the drug instructions carefully or follow the doctor's advice.

Clopidogrel adverse reactions

Common adverse reactions are gastrointestinal bleeding, neutropenia, abdominal pain, loss of appetite, gastritis, constipation, and rash. Occasionally thrombocytopenic purpura.

Clopidogrel precautions

Elderly patients do not need to adjust the dose. It can be secreted by breast milk, so pregnant women and lactating women should weigh the pros and cons. Use with caution in patients with liver and kidney damage.

Clopidogrel contraindications

Allergic to this product, patients with ulcer disease and patients with intracranial hemorrhage are prohibited.

Clopidogrel drug interactions

Aspirin, naproxen, warfarin, heparin, thrombolytic drugs, evening primrose oil, curcumin, capsaicin, black leaf chamomile, ginkgo, garlic, salvia, etc. can increase the bleeding risk of this product. Omeprazole can reduce the blood concentration of this product and increase the risk of cardiovascular events.

Clopidogrel

Tablet: 25mg, 75mg

Clopidogrel Pharmacopeia Introduction

[Identification] (1) Take 30mg of this product, add 1ml of water to dissolve, take 1-2 drops of solution, and place in a 1ml test tube containing a formaldehyde sulfate solution (add 1 drop of formaldehyde solution to 1ml of sulfuric acid, shake), the surface is Violet-red. (2) The infrared light absorption spectrum of this product should be consistent with the control spectrum (spectrum set 1220). (3) In the chromatogram recorded under the relevant substance, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the system suitability solution. (4) Identification of sulfates in aqueous solution (1g 1ml) (1) Reaction (Appendix III). The above two items (1) and (2) are optional. [Check] Acidity: Take 0.2g of this product, slowly add 30ml of water and continue to shake the drug to dissolve. Determine according to law (Appendix VI H). The pH should be 1.5 ~ 2.5 Clarity and color of the solution should be 0.5g of this product. After adding 10ml of methanol to dissolve, the solution should be clear and colorless; if color is developed, it should not be deeper than the yellow color standard solution (Appendix A first method). Take about 65mg of this substance, put it into a 10ml volumetric flask, add mobile phase A-acetonitrile (40:60) to dissolve and dilute to the mark, as a test solution; take a precise amount of 1ml, use mobile phase A-acetonitrile (40 : 60) Dilute to 100 ml, and then accurately measure 1 ml, place it in a 10 ml measuring flask, and dilute to the mark with mobile phase A-acetonitrile (40:60) as a control solution. Also take the appropriate amount of clopidogrel hydrogen sulfate reference, clopidogrel impurity reference and clopidogrel impurity reference, accurately weigh, add mobile phase A-acetonitrile (40:60) to dissolve and dilute to make each 1ml A mixed solution containing 6.5 mg of clopidogrel hydrogen sulfate, 0.013 mg of clopidogrel and 0.0195 mg of clopidogrel , shake well, and use it as a system suitability solution. Test according to high performance liquid chromatography (Appendix VD). Octadecylsilane-bonded silica gel as filler; methanol-sodium pentanesulfonate solution (0.96g / L, pH adjusted to 2.5 with phosphoric acid) (5:95) as mobile phase A, methanol-acetonitrile (5:95) is mobile phase B; the flow rate is 1.0 ml per minute; the column temperature is 30 ° C; the detection wavelength is 220 nm. Gradient elution was performed according to the following table. Take 10l of the system suitability solution, inject it into the liquid chromatograph, and record the chromatogram. The order of peaks is clopidogrel impurity , clopidogrel and clopidogrel impurity ; clopidogrel peak and clopidogrel impurity separation The degree should meet the requirements. Take 10 l of the control solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 15% of the full range; and then accurately measure 10 l each of the test solution and the control solution, and inject them into the liquid chromatograph , Record the chromatogram. If there are impurity peaks in the chromatogram of the test solution, the peak area of clopidogrel impurity should not be greater than 2 times (0.2%) the main peak area of the control solution, and the peak area of clopidogrel impurity should not be greater than 3 (0.3%), the area of other single impurity peaks shall not be larger than the main peak area of the control solution (0.1%), and the sum of the peak areas of each impurity shall not be greater than 5 times (0.5%) the main peak area of the control solution. Any peak that is less than 0.5 times (0.05%) of the main peak area of the control solution in the chromatogram of the test solution can be ignored.

Enantiomers: Take about 100mg of this product, weigh it accurately, place it in a 50ml volumetric flask, add a small amount of absolute ethanol to dissolve it, and then dilute it to 50ml with absolute ethanol-heptane (1: 1). Test solution; take 1ml precisely, place in a 100ml volumetric flask, dilute to the mark with absolute ethanol-heptane (1: 1), shake well, and use it as a control solution. Test according to high performance liquid chromatography (Appendix VD). Cellulose-tris (4-methylbenzoate) silica gel was used as the filler; absolute ethanol-heptane (15:85) was used as the mobile phase; the flow rate was 0.8 ml per minute; the detection wavelength was 220 nm. Take clopidogrel hydrogen sulfate, clopidogrel impurity and clopidogrel impurity , weigh them accurately, add a small amount of absolute ethanol to dissolve, and dilute with anhydrous ethanol-heptane (1: 1) to make 1ml. A mixed solution containing 2.0 mg of clopidogrel hydrogen sulfate, 0.02 mg of clopidogrel II and 0.01 mg of clopidogrel III as a system suitability solution. Take 10 l into the liquid chromatograph and record the chromatogram. The order of the peaks is clopidogrel impurity II (R), clopidogrel impurity III and clopidogrel impurity II (S), and two pairs of clopidogrel impurity II. The resolution of the enantiomeric peak from clopidogrel impurity III should be greater than 2.0, and the signal-to-noise ratio of clopidogrel impurity III peak should be greater than 20. Precisely measure 10 l of each of the above two solutions, and inject them into the liquid chromatograph respectively. Record the chromatogram to 1.25 times the retention time of the main component. 0.5 times the area (0.5%). Residual solvents: ethanol, acetone, dichloromethane and ethyl acetate. Take about 2.5g of this product, weigh it accurately, put it in a 25ml measuring flask, add N, N-dimethylacetamide to dissolve and dilute to the mark. Measure 10ml, place it in a headspace bottle, and seal it as the test solution; take an appropriate amount of ethanol, acetone, dichloromethane, and ethyl acetate, accurately weigh, add N, N-dimethylacetamide to dissolve and dilute A mixed reference solution containing 0.5 mg of ethanol, 0.2 mg of acetone, 0.06 mg of dichloromethane, and 0.5 mg of ethyl acetate was prepared in each 1 ml. 10 ml was accurately measured, placed in a headspace bottle, sealed, and used as a reference solution. Measure according to the residual solvent determination method (Appendix P second method). Capillary column with 6% cyanopropyl-phenyl-94% dimethyl polysiloxane (or similar polarity) as the fixed liquid; the initial temperature is 60 ° C, maintained for 6 minutes, and then 70 minutes per minute The temperature rises to 200 ° C for 3 minutes; the inlet temperature is 200 ° C; the detector temperature is 250 ° C; the headspace bottle equilibrium temperature is 60 ° C and the equilibration time is 30 minutes; the split ratio is 10: 1. The reference solution was injected in the headspace, and the chromatogram was recorded. The resolution between the peaks should meet the requirements. Take the reference solution and the test solution separately for headspace injection, record the chromatogram, and calculate the peak area according to the external standard method, which should meet the requirements. Formic acid takes 0.1g of this product, weighed accurately, put it into a 50ml measuring bottle, and slowly add the diluent [to a 0.05mol / L potassium dihydrogen phosphate solution (adjust the pH to 2.0 with phosphoric acid)-methanol (93: 7) ] Wet a small amount. After standing for about 10 minutes, shake the drug to dissolve it, then dilute it to the mark with a diluent, shake it well, and use it as a test solution. Take an appropriate amount of formic acid, accurately weigh it, and dilute it with a diluent to make a solution containing about 0.01 mg per 1 ml as a reference solution. Test according to high performance liquid chromatography (Appendix VD). Octadecylsilane-bonded silica gel as filler; 0.05mol / L potassium dihydrogen phosphate solution (pH adjusted to 2.8 with phosphoric acid) as mobile phase A, and methanol as mobile phase B; flow rate is 1.0ml per minute ; Detection wavelength is 215nm. Gradient elution was performed according to the following table. Precisely measure 50 l each of the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatogram. Calculated by the peak area based on the external standard method, the content of formic acid should not exceed 0.5%.

Loss on drying: Take this product and dry to constant weight at 105 ° C. Lose weight should not exceed 0.5% (Appendix L). Take 1.0g of this product and check it according to law (Appendix N). The remaining residue should not exceed 0.1%. The heavy metal shall be taken as the residue left under the burning residue, and shall be inspected in accordance with the law (Appendix H Second Law). The content of heavy metal shall not exceed 20 parts per million. [Content determination] Take about 0.16g of this product, weigh it accurately, add 50ml of mixed solution [acetone-methanol-water (10:10:30)], dissolve it, and apply potentiometric titration method (Appendix A), and use hydroxide Titrate the sodium titration solution (0.1mol / L) to the end point (precipitation is formed during the titration), and correct the result of the titration with a blank test. Each 1ml of sodium hydroxide titration solution (0.1mol / L) is equivalent to 20.99mg of C16H16ClNO2S · H2SO4. [Category] Platelet inhibitors. [Storage] shading and sealed.

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