Draw the Frame or General Formula of Each Drug Group (If Any); Structural Formula of Substances in the Chapter.

Perform TLC to identify and test for related impurities.

Quantitative

Measure the absorbance at λmax=231 nm in alcohol medium, calculate the result according to A(1%, 1 cm)=500.

Uses:

Stable (3)-benzoate ester form (-OH phenol lock), has suitable pharmacokinetics, gradually releases estradiol in the body.

Estradiol monobenzoate is more therapeutically potent than estrone or estropipate (which are salts of esters).

(estrone, estriol, equilin . . . ) still have an effect, so estradiol monobenzoate has a long-lasting effect (several days).

Assign:

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Used as replacement therapy after menopause, ovarian failure, after oophorectomy. Replaces estrone or etropipate in most cases.

For intramuscular (IM) injection in ethyloleate or a suitable ester or in oil. Usually 0.1% concentration, 1 mg or 5 mg ampoules.

Dosage: Depends on the specific case, for example:

Postmenopausal disorders, anti-postmenopausal osteoporosis... 5 mg/time/3-4 weeks. Also used in tablet form (usually 0.1 mg tablets) to take orally at a dose of 0.3-0.6 mg/24 hours, depending on the case.

1.1.2. Semi-synthetic estrogens

General characteristics: More persistent in metabolic effects, stronger and often longer lasting, but more frequent and stronger adverse effects.

Ethinylestradiol and derivatives.

ETHINYLESTRADIOL

Brand name : Estinyl; Progynon; Estigyn

Recipe :

C 20 H 24 O 2 equation: 296.41

Scientific name : Dihydroxy-3β, 17β-ethiny-17α-estratrien 1,3,5(10). Is 17α-ethinylestradiol.

Preparation : Semi-synthetic according to the reaction:

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Estrone Ethinyl estradiol

Properties :

The preparation is in the form of a white to cream colored refined powder. Insoluble in water, soluble in alcohol, ether, chlorobrom, in alkali metal hydroxide solution.

Melting point: 181 – 185 o C (if the preparation is in polymorphic form, the melting point is 142 – 146 o C).

Qualitative:

Test by TLC, together with relevant impurity test.

Color reaction with H 2 SO 4 (1 mg of preparation/1 ml of concentrated H 2 SO 4 ): gives orange-red color, examines under 365 UV lamp with green fluorescence; dilute with water (add 10 ml), gives purple color and purple precipitate.

20

UV spectrum has Amax=281 nm with A(1%,1 cm)=69-73(C 0.01 , MeOH). It is a choleretic agent with [α] D =-274 – 30 (C 5 , pyridine).

Related impurities test : By TLC, the main impurity was estrone.

Quantitative :

Based on the reaction to create silver salt AgNO 3 , releasing HNO 3 ; quantify HNO 3 with 0.1N NaOH; determine the end point with a potentiometer.

Uses :

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The presence of 17α-ethinyl inhibits the action of liver metabolizing enzymes on the molecule, thus maintaining its strong oral effect. When injected, the effect of ethinylestradiol is equivalent to estradiol, but if both are taken orally, the effect is 15-20 times stronger than estradiol. Ethinylestradiol is one of the most potent oral estrogens.

Ethinylestradiol has antiovulatory effects at relatively low doses, and is most widely used in combination with progestins for oral contraception.

Assign:

Has similar indications to estradiol and estradiol ester derivatives. Some common indications are:

- Postmenopausal replacement therapy: 0.01-0.02 mg/24h (with progestin). However, for this indication, natural estrogen is preferred.

- Female hypogonadism, prostate cancer, breast cancer (in postmenopausal women), 0.1-1mg/time x 3 times/24 hours.

- In combined oral contraceptives: ethinylestradiol – levonorgestrel.

Dosage form:

Tablets 0.02mg; 0.05mg; 0.5mg (used to treat cancer); round tablets containing ethinylestradiol.

Etherification of (3)-OH to (3)-OCH 3 gives mestranol, and (3) gives quinestrol (trade name Estrovis), both of which are prodrugs of ethinylestradiol, administered orally with prolonged action.

 Synthetic non-steroidal substances have estrogenic and anti-estrogenic effects.

Due to the size, configuration and position of the functional groups of these substances relative to estradiol, they have estrogenic or antiestrogenic effects. The structural difference in the antiestrogenic substances is the addition of side chains. Chlorothrianixen, diethylstilbestrol, are classic substances, have strong effects but are highly toxic. Antiestrogenic substances have the effect of stimulating ovulation and are used to treat infertility, while raloxifene also has the effect of maintaining the balance of bone metabolism and lipid metabolism (reducing LDL).

CHLOMIPHEN CITRATE

Brand name : Serophen, clomid, milophen.

Recipe :

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An anti-estrogen most widely used for the treatment of infertility; taken in 5-day courses. First course: Starting on the 5th day of the menstrual cycle: 50mg/24 hours (5 consecutive days).

Clomiphene is also used to treat postmenopausal breast cancer.

In the above formula: replace –Cl with –C 2 H 5 , replace –N(C 2 H 5 ) 2 with –N(CH 3 ) 2 and change the position of the two aromatic rings attached to C, so that –C 2 H 5 and –C 6 H 4 -O-CH 2 -CH 2- N(CH 3 ) 2 have the front configuration, we have tamoxifen citrate (trade name Novaldex). This substance has the same effect and use as clomiphene citrate, mainly for treating infertility.

1.2. Progestins

The natural hormone is progesterone, secreted by the corpus luteum and is abundant during pregnancy due to the placenta. Semi-synthetic substances are more stable, have a strong, long-lasting effect and can be taken orally. All of the above substances are collectively called progestins (progesterone), in structure they have a pregnan framework.

1.2.1. Progesterone PROGESTERON

Trade name : Lutein

Recipe :

C 21 H 30 O 2 equation: 314.47

Scientific name : Pregn-4-en-3,20-dion or diceto-3,20-pregnen-4

For the first time, in 1934, A. Butenandt extracted gold from pig's body.

Preparation :

In industry, semi-synthetic from diosgenin (60% yield) or stigmasterol:

Diosgenin DPA

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(dehydroprednenolone)

Prednenolone

Nature:

20

The preparation is in the form of a white crystalline powder, insoluble in water, soluble in oil, alcohol, ether, chloroform. Melts at 126 – 131 o C, the polymorph melts at 121 o C. Hydrophilic, [α] D = +

175 ÷+ 183 o (C 2 , dioxin).

Qualitative :

- Zimmermann reaction (of ketone function): gives purple-red color.

- Hydrazone formation reaction:

+ Preparations

+ 2,4 dinitrophenyl hydrazine 1/ EtOH, in the presence of HCl

+ Heat

- Reaction to form dioxime progesterone, precipitate recrystallized in methanol, measured melting point 134-137 o C:

+ Preparations

+ HO – NH 2 .HCl/EtOH and OH -

+ Heat

- Measure UV spectrum from methanol solution, measured in parallel with standard.

- Measure IR spectrum, compared with standard spectrum

Use TLC (for identification and testing of related impurities)

Quantitative :

- Precipitation weighing or photometric measurement

- HPLC (USP 2000) is the common method.

Uses :

- Is the main hormone of the body. Used as a replacement treatment for the following cases: corpus luteum deficiency, menstrual disorders, amenorrhea, painful menstruation, uterine bleeding, underdeveloped and inactive reproductive organs, infertility; with an average dose of 5-10mg/24h, combined with estrogen.

- Especially to prevent miscarriage: intramuscular injection 25 g/24 hours, continuously or 25-100 mg (can be increased if necessary)/time x 2 times/week.

- Endometrial cancer: use high doses.

Dosage form :

213