What Is Levonorgestrel?

The chemical formula of levonorgestrel is (a) -13-ethyl-17-hydroxy-18,19-bisdesmethyl-17-pregn-4-en-20-acetyl-3-one. It is white or almost white crystalline powder; odorless and tasteless. Dissolved in chloroform, slightly soluble in methanol, insoluble in water.

Chinese name: Levonorgestrel
Foreign name: Levonorgestrel

CAS number: 797-63-7
Molecular formula: C21H28O2

Brief introduction of levonorgestrel compounds

Levonorgestrel Basic Information

Chinese name Levonorgestrel

Chinese alias: D ()-17-ethynyl-17-hydroxy-18-methylestrone-4-en-3-one; (-)-norethrelone Ketone; 13-Ethyl-17-ethynyl-17-hydroxygon-4-en-3-one; D (-)-norethrelone

English name: Levonorgestrel

English alias: postinor; microluton; Norgeston; Levonorgestrel; [3H] -Levonorgestrel; [18,19-Dinorpregn-4-en-20-yn-3-one-13-ethyl-17-hydroxy-, (17.. )-(-)-]

CAS number: 797-63-7

MDL number: MFCD00199013

EINECS number: 212-349-8

RTECS number: JF8225000

PubChem number: 24857181

Molecular formula: C ₂₁ H ₂₈ O ₂

Structural formula:

Molecular weight: 312.44600

Exact mass: 312.20900

PSA: 37.30000

LogP: 3.88260 ^[1]

Physicochemical Properties of Levonorgestrel

Appearance and properties: white crystalline powder

Density: 1.13 g / cm

Melting point: 206

Boiling point: 459.1 at 760 mmHg

Flash point: 195.4

Refractive index: 1.571 ^[1]

Storage conditions: 2-8

Levonorgestrel Safety Information

Customs code: 2937290090

Danger category code: R20 / 21/22; R40

Safety instructions: S22-S36 ^[1]

Levonorgestrel molecular structure data

1. Molar refractive index: 90.18

2. Molar volume (m3 / mol): 274.3

3. Isometric Zhang Rongrong (90.2K): 723.2

4. Surface tension (dyne / cm): 48.3

5. Dielectric constant:

6. Dipole distance (10-24cm3):

7. Polarizability: 35.75 ^[2]

Calculated chemical data for levonorgestrel

1. Reference value for calculation of hydrophobic parameters (XlogP): 3.3

2. Number of hydrogen-bonded donors: 1

3. Number of hydrogen bond acceptors: 2

4. Number of rotatable chemical bonds: 2

5. Number of tautomers: 8

6. Topological molecular polar surface area (TPSA): 37.3

7, the number of heavy atoms: 23

8. Surface charge: 0

9. Complexity: 609

10. Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 6

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0 ^[2]

15. Number of covalent bond units: 1

Levonorgestrel use

Progestogens are used for irregular menstruation, uterine functional bleeding, and endometrial displacement. ^[1]

Levonorgestrel Pharmacopoeia Standard

Source (name) and content (potency) of levonorgestrel

This product is (a) -13-ethyl-17-hydroxy-18,19-bisdesmethyl-17-pregn-4-en-20-yne-3-one. Containing C21H28O2 should be 97.0% to 103.0%. ^[3]

Levonorgestrel traits

This product is white or off-white crystalline powder; odorless and tasteless.

This product is soluble in chloroform, slightly soluble in methanol, and insoluble in water. ^[3]

Levonorgestrel specific rotation

Take this product, weigh it accurately, add chloroform to dissolve and quantitatively dilute it to make a solution containing about 20mg per 1ml, and measure it according to law (Appendix VI E of the Pharmacopoeia Part II of 2010 Edition). The specific rotation is -30 ° C to -35 . ^[3]

Levonorgestrel identification

(1) In the chromatogram recorded under the content determination item, 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) The infrared absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Drugs" 726). ^[3]

Levonorgestrel test

Ethynyl

Accurately weigh about 0.1g of this product, add 40ml of tetrahydrofuran to dissolve, add 10ml of 5% silver nitrate solution, potentiometric titration method (Appendix A of Pharmacopoeia Part II of 2010 Edition), and use sodium hydroxide titration solution (0.1mol / L) Titration. Each 1ml of sodium hydroxide titration solution (0.1mol / L) is equivalent to 2.503mg of ethynyl (-CCH). This product should contain acetylene groups from 7.81% to 8.18%.

relative substance

Take this product, add the mobile phase to dissolve and make a solution containing about 75g per 1ml as the test solution; take 2ml precisely, place it in a 100ml volumetric flask, dilute to the mark with the mobile phase, and shake it as the control solution . According to the chromatographic conditions under the content determination item, 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 20% of the full scale. Then accurately measure 20 l each of the test solution and the control solution, and respectively inject them into the liquid chromatograph, and record the chromatogram to twice the retention time of the main component chromatographic peak. If there is an impurity peak in the chromatogram of the test 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 (2.0%). ^[3]

Determination of Levonorgestrel

It was determined by high performance liquid chromatography (Appendix D, Part Two of the Pharmacopoeia, 2010 Edition).

Chromatographic conditions and system suitability tests

Octadecylsilane-bonded silica gel was used as the filler; acetonitrile-water (70:30) was used as the mobile phase; the detection wavelength was 240 nm. Take levonorgestrel and megestrol acetate, add mobile phase to dissolve and dilute it to make a solution containing 75 g of levonorgestrel and 0.5 mg of megestrol acetate in 1ml, take 20 l into the liquid chromatograph , Record the chromatogram. The theoretical plate number is calculated to be not less than 2000 according to the levonorgestrel peak, and the resolution of the levonorgestrel peak and the megestrol acetate peak should meet the requirements. ^[3]

Assay

Take an appropriate amount of this product, accurately weigh, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 75g per 1ml, shake well, and accurately measure 20l into the liquid chromatograph and record the chromatogram; Ketone reference substance, the same method. Calculate the peak area according to the external standard method.

Levonorgestrel Drug Analysis

Method name: Levonorgestrel API-Levonorgestrel-High Performance Liquid Chromatography

Scope of application: This method uses high performance liquid chromatography to determine the content of levonorgestrel in the levonorgestrel bulk drug.

This method is applicable to levonorgestrel drug substances.

Principle of the method: After the test product is diluted with mobile phase and added with an internal standard, it is subjected to high-performance liquid chromatography for chromatographic separation. The ultraviolet absorption detector is used to detect the peak area of levonorgestrel at a wavelength of 240nm and calculate its content. .

Reagent: acetonitrile

Equipment: 1. Instrument 1.1 High Performance Liquid Chromatograph

1.2 Column

Octadecylsilane-bonded silica gel is used as a filler, and the number of theoretical plates calculated based on the levonorgestrel peak should not be less than 2000.

1.3 UV absorption detector

2.Chromatographic conditions

2.1 Mobile phase: Acetonitrile water = 7030

2.2 Detection wavelength: 240nm

2.3 Column temperature: room temperature

Sample preparation: 1. Preparation of internal standard solution

Accurately weigh an appropriate amount of megestrol acetate and add acetonitrile to make a solution containing about 1 mg per 1 mL, which is the internal standard solution.

2. Preparation of reference solution

Precisely weigh about 7.5mg of levonorgestrel reference substance, place it in a 50mL volumetric flask, dissolve and dilute to the mark with mobile phase, shake well, and accurately measure 2mL each of the solution and the internal standard solution. 3. Test solution Preparation

Approximately 7.5 mg of the test sample was accurately weighed, placed in a 50 mL volumetric flask, dissolved in mobile phase and diluted to the mark, and shaken. Precisely weighed 2 mL each of the solution and the internal standard solution, and mixed to obtain the test solution.

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.

Operation steps: Precisely draw 20 mL of each of the reference solution and the test solution, and inject them into a high-performance liquid chromatograph. Use an ultraviolet absorption detector to measure the peak area of levonorgestrel (C21H28O2) at a wavelength of 240 nm and calculate its content .

Indications of levonorgestrel function

It is mainly used as a family visit contraceptive and emergency contraceptive. It is used in combination with estrogen and is short-acting and long-acting.

Oral contraceptives have the effect of inhibiting ovulation and are currently the most widely used at home and abroad. It can also be used to treat irregular menstruation, uterine functional bleeding and endometriosis. Adapt to symptoms

This product and ethinyl estradiol form a composite film or double-photograph or triple-photograph, used as a short-acting oral contraceptive, and can be used as a variety of long-acting contraceptives by changing the dosage form. Oral absorption is rapid, the blood concentration reaches a peak after 0.5 to 2 hours, and T1 / 2 is 10 to 24 hours. The protein binding rate is 93 to 95%, and the bioavailability is 100%. Mostly distributed in the liver, kidney, ovary and uterus, metabolites are mainly excreted from urine and feces in the form of glucuronate and sulfate. It can be used as a short-acting oral contraceptive compound or double-photograph and triple-photograph with ethinyl estradiol. The composite film reduced the HDL significantly, while the two photos and three photos had less influence; the three photos reduced the amount of the product by about 40% per cycle and had fewer adverse reactions. This product is currently the most widely used oral contraceptive in the world for women's contraception. Since its implantation in Finland in 1983, it has been approved for use in many countries. The experience of 55,000 implanters indicates that the pregnancy rate is very low, accumulating about 3.9% over 5 years.

Pharmacological effects of levonorgestrel

Levonorgestrel (LNG) is a fully synthesized, powerful progestin, an optically active form of racemic norgestrel, which is 1 times more active than norgestrel and about 100 times more than norgestrel. For this reason, the dose can be halved and the adverse reactions can be reduced. Levonorgestrel mainly acts on the hypothalamus and pituitary gland, which significantly reduces or disappears the peak of FSH and LH levels in the middle of menstruation. The ovaries do not ovulate, and have significant anti-estrogenic activity. With estrogen activity. Can thicken cervical mucus and prevent sperm penetration. It has extremely strong progestin activity for endometrial transformation, which can make the endometrium thin, the endometrial epithelial cells have a low columnar shape, and poor secretion function, which is not conducive to implantation of pregnant eggs. LNG also has a certain androgenic activity and protein assimilation effect, which can inhibit ovulation by oral or subcutaneous injection.

LNG was absorbed quickly and completely after oral administration, and the absorption t1 / 2 was 0.29 hours. Peak blood drug can be reached within 0.5-2 hours after taking the medicine. Oral LNG has almost no first-pass effects. The whole body bioavailability ratio F (AuCo / AuCiv) ranges from 0.87 to 0.99. The decrease in LNG concentration in the blood was in the form of a double exponential curve, with a distribution of t1 / 2 of 50-60 minutes and a elimination of t1 / 2 of 8.8-11 hours. LNG has a plasma clearance of 152-176L / d, which is significantly slower than norethindrone. LNG has a highly specific binding to plasma sex hormone globulin (SHBG). When used in combination with estrogen, the latter can stimulate the liver to synthesize SHBG, which can significantly increase LNG levels in the blood. The protein binding rate is 93% -95%, and the bioavailability is 100%. It can reduce high density lipoprotein (HDL) and increase low density lipoprotein (LDL). After breastfeeding women take LNG, the ratio of drug concentration in blood to milk is 100: 15-25. The mother took 150 g of LNG daily, and there was no accumulation of LNG in the baby. This product is metabolized in the liver. The main metabolites are 3, 5 and tetrahydromethyl norethisterone. Most of the excreted metabolites are glucuronic acid and sulfuric acid conjugates.

Pharmacokinetics of Levonorgestrel

Oral easily absorbed from the gastrointestinal tract. Oral levonorgestrel was 1 mg, and plasma concentrations were measured at 2, 8, and 24 hours, which were 8.1 ng / ml, 3.8 ng / ml, and 1.3 ng / ml, respectively. t1 / 2 is 5.5 to 10.4 hours. The main distribution after oral administration: liver, kidney, ovary and uterus. Metabolized mainly in the liver. The metabolites are mainly 3, 5-tetrahydromethyl norethisterone. Most can be eliminated in 24 hours, and there is no retention in the body.

Levonorgestrel indication

It is used for emergency contraception in women, that is, when there are no protective measures or accidental errors in other contraceptive methods. ^[4]

Levonorgestrel usage and dosage

This product is the optically active part of levonorgestrel, and its activity is 1 times stronger than that of norethisterone, so the dosage can be doubled, and the adverse reactions are also relatively weakened. Levonorgestrel is a short-acting oral contraceptive. But they are not used alone, but combined with ethinyl estradiol. 1. From the day of menstruation, take medicine once on lunch on the fifth day, take a second medicine every 20 days, or take one tablet each on the fifth and tenth days of menstruation. Tablets, usually with withdrawal bleeding 6 to 12 days after taking the drug. If the adverse reaction is serious after taking the medicine, the dosage reduction tablet can be switched to the fourth cycle. 2. When the original short-acting oral contraceptive was changed to the long-acting contraceptive, the long-acting contraceptive pill can be taken the next day after taking 22 tablets, and then one tablet per month will be taken on the same date as the long-acting contraceptive.

Generally taken before bedtime, side effects can be reduced.

If breakthrough bleeding occurs during the first half of the medication, you can take 0.01mg of ethinyl estradiol every night until the end of the cycle; if the bleeding occurs in the second half of the medication, you can take one contraceptive pill daily until the drug is stopped; If the amount of bleeding is like menstrual flow, the drug should be discontinued and treated according to menstruation.

If the menstruation has not been performed within 7 days, the next cycle of medicine can be started.

Those who have not taken menstrual cycles for two cycles should find out the cause of amenorrhea and exclude pregnancy.

The daily time of taking contraceptives should be the same, so as to avoid large fluctuations in blood concentration and affect the contraceptive effect. ^[5]

Adverse effects of levonorgestrel

1. Common menstrual cycle irregularities, drip or breakthrough bleeding, amenorrhea, nausea, vomiting, headache, breast swelling, acne, weight gain, depression, lowering HDL, breakthrough bleeding, amenorrhea, etc. Others are similar to norethindrone.

2. Rare headaches, pain in the chest, arms, legs, especially gastrocnemius muscles, weakness in arms and legs, numbness or pain, sudden or unexplained shortness of breath, sudden speech inarticulation, sudden vision changes, diplopia, blindness to varying degrees, etc. , Mental depression, stomach pain, conjunctival or yellow skin staining, suspected hepatitis; bile duct obstruction or liver tumors, allergic dermatitis and galactorrhea.

3 Attention should be paid to the following conditions, such as changes in gastric appetite, swelling of the ankles and feet, abnormal tiredness and weakness, and breast pain. ^[5]

Levonorgestrel considerations

1. Progestogen can cause fetal congenital malformations, and should not be taken during pregnancy, especially within 4 months of pregnancy.

2. Progestogen can be excreted through breast milk and should not be taken by lactating women. 3 Interference with diagnosis can reduce the measured value of urinary pregnancy diol, and increase the measured values of serum alkaline phosphatase, plasma amino acid and urea nitrogen.

4 Breast cancer and reproductive organ cancer should be disabled in the following cases, unless some advanced cancer is used as palliative treatment. liver disease or abnormal liver function. (3) Cannot be used in suspicious pregnancy, and a pregnancy test should be performed in time to confirm the diagnosis. expired abortion. A history of thrombophlebitis, thromboembolism or cerebral hemorrhage. Irregular vaginal bleeding without a clear diagnosis.

5. The following conditions should be used with caution such as asthma, myocardial contractility or cardiac insufficiency, epilepsy, migraine, abnormal renal function. Progestogen can exacerbate illness due to retention of body fluids, depression or history of this disease, diabetes, etc.

6. Long-term medication users should pay attention to: check liver function, vaginal shedding cell smear, etc. Check every 6-12 months, paying special attention to breast and pelvic organs.

7. Dosing instructions: Long-term use can change the menstrual cycle and cause irregular bleeding. Dosage should be based on a 28-day cycle. (3) It should not be used as a withdrawal test when suspicious early pregnancy. ^[4]

Levonorgestrel drug interactions

drugs that affect the effectiveness of contraception;

Antibiotics inhibit the intestinal bacterial reproduction, reduce the breakdown of hormone conjugates, and reduce intestinal and liver circulation;

Drugs that induce liver drug enzymes such as rifampicin, hypnotic and anticonvulsants, antipyretics and analgesics;

Tricyclic antidepressants compete with the product for common metabolic enzymes in the liver.

Drugs that are used in combination with contraceptives and whose effects are affected;

The antihypertensive effect of antihypertensive drugs is reduced;

The anticoagulant effect of anticoagulant is reduced;

The efficacy of hypoglycemic drugs (such as insulin and oral hypoglycemic drugs) in reducing diabetes is reduced;

The effect of tricyclic antidepressants is enhanced.

In contrast, the new snornogestone progesterone drop pills of Guangdong Taikang Pharmaceutical Co., Ltd., such as with other drugs (especially phenobarbital, phenytoin, rifampicin, carbamazepine, and macrolide antibiotics) , Imidazole antifungal drugs, cimetidine and antiviral drugs, etc.) Drug interactions may occur at the same time, please consult a physician or pharmacist when using them. ^[4]

Levonorgestrel Storage

Store in a cool, dry place, protected from light and sealed. ^[5]

Common dosage forms of levonorgestrel

Neosnow levonorgestrel drip pill: avoids vomiting of 11% of conventional contraceptives and 6% of contraceptive failures. The onset time was accelerated by 37.8 minutes, the bioavailability (effective absorption rate) was increased by 9.7%, and there were basically no side effects such as nausea and vomiting. There have been no cases of contraceptive failure so far. Each tablet contains levonorgestrel 0.75mg, taking method: oral. Within 72 hours of unprotected sexual life or contraceptive failure, take 2 capsules orally once; or take 1 capsule for the first time, and take the second capsule every 12 hours. The sooner you take the medicine, the better the effect of preventing pregnancy.

Compound levonorgestrel tablets: Each tablet contains 0.15mg levonorgestrel and 0.03mg ethinylestradiol.

Biphasil: Levoprogesterone: 0.05mg per tablet on the 11th

And ethinyl estradiol 0.05mg, the next 10 days containing the corresponding drugs 0.125mg and 0.05mg. ^[5]

Danmei (levonorgestrel enteric-coated tablets)

Three photos of Levonorgestrel (Triphasil): Each tablet contains 0.05mg of the product and 0.03mg of ethinyl estradiol on the first 6 days, each tablet contains 0.075mg and 0.04mg of the corresponding drug on the 5th day, and each tablet contains the corresponding drug on the 10th day 0.125 mg and 0.03 mg.

Levonorgestrel contraceptive ring: 5mg.

Levonorgestrel implants (Norplant) come in two forms: Type I consists of 6 roots, each containing 36mg of medicine, which can effectively prevent contraception for 5 years; Type II consists of 2 roots, containing 70mg of medicine, which can effectively prevent contraception. 3 years. ^[6]