Exemestane (trade name Aromasin) is a highly effective and selective third-generation aromatase inhibitor, mainly used to treat hormone-dependent breast cancer in postmenopausal women. As a steroid compound, it blocks estrogen synthesis by irreversibly binding to aromatase, thereby inhibiting tumor growth. The following is a systematic analysis of Exemestane API from the aspects of chemical properties, pharmacological properties, production process, quality control, application areas and market prospects.
#### 1. Chemical properties and basic information
1. **Chemical structure**
- The chemical name of Exemestane is **6-Methylenandrosta-1,4-diene-3,17-dione** (6-Methylenandrosta-1,4-diene-3,17-dione), which is an androstane derivative.
- Molecular formula: **C20H24O2**
- Molecular weight: **296.4 g/mol**
- CAS number: **[107868-30-4]**
2. **Physical properties**
- Appearance: White to off-white crystalline powder.
- Melting point: about 195-198 degree .
- Solubility: Almost insoluble in water, easily soluble in chloroform and dimethyl sulfoxide (DMSO), slightly soluble in ethanol and methanol.
- Stability: sensitive to light and humidity, needs to be sealed and stored away from light, and a low-temperature dry environment is required for long-term storage.
3. **Synthetic precursors and intermediates**
- The key intermediates for the synthesis of exemestane include **androstenedione (AD)** and **epiandrosterone**, and the target structure is obtained by chemical modification (such as methylation at C6).
#### 2. Pharmacological properties
1. **Mechanism of action**
- **Aromatase inhibitor**: Exemestane covalently binds to the active site of aromatase, irreversibly inhibiting its ability to convert androgens (such as testosterone) into estrogens (estradiol, estrone), reducing estrogen levels in the body by more than 95%.
- **Steroid structure advantage**: Compared with non-steroidal inhibitors (such as anastrozole), its steroid skeleton is similar to endogenous substrates, with higher affinity and lower drug resistance.
2. **Pharmacodynamics and pharmacokinetics**
- **Bioavailability**: Rapid oral absorption, peak time (Tmax) of about 1-2 hours, bioavailability of 42%.
- **Metabolic pathway**: Oxidative metabolism by liver CYP3A4 enzyme to inactive metabolites such as 17-hydroxyexemestane, with a half-life of about 24 hours.
- **Excretion**: About 42% is excreted through the kidneys and 42% through the feces. No dosage adjustment is required for patients with renal insufficiency.
3. **Toxicology and safety**
- Common side effects include hot flashes, joint pain, fatigue, and serious adverse reactions are rare (such as osteoporosis and elevated liver enzymes).
- Clinical studies have shown that its cardiovascular toxicity is lower than that of tamoxifen, and long-term use is well tolerated.
#### 3. Production process and optimization
1. **Synthesis route**
- **Route 1: Using androstenedione (AD) as the starting material**
1. AD is hydroxylated by microorganisms to generate 11 -hydroxyandrostenedione;
2. A methylene group is introduced at the C6 position (such as the Wittig reaction);
3. Oxidative dehydrogenation forms a 1,4-diene structure.
**Advantages**: Shorter steps and higher yield (about 50%).
- **Route 2: Chemical Total Synthesis**
Using epiandrosterone as raw material, the steroid skeleton is constructed through multi-step reactions.
**Advantages**: Avoiding biotransformation steps, suitable for large-scale production.
**Disadvantages**: The steps are cumbersome and the total yield is low (about 30%).
2. **Process Optimization Direction**
- **Green Chemistry**: Using catalytic hydrogenation to replace traditional oxidants to reduce the discharge of three wastes.
- **Continuous Flow Technology**: Improve reaction efficiency and reduce energy consumption.
- **Crystallization Process Improvement**: Improve the purity of the crystal form through solvent screening (such as acetone/water system).
####4. Quality control and standards
1. **Quality standards**
- Comply with **USP (United States Pharmacopoeia)**, **EP (European Pharmacopoeia)** and **ChP (Chinese Pharmacopoeia)** standards, key indicators include:
- Purity: Greater than or equal to 99.0% (HPLC method);
- Impurities: single impurity Less than or equal to 0.1%, total impurities Less than or equal to 0.5%;
- Loss on drying: Less than or equal to 0.5%;
- Residual solvent: Meet ICH Q3C requirements (such as methanol <3000 ppm).
2. **Analytical methods**
- **HPLC-UV**: C18 chromatographic column, mobile phase is acetonitrile-water gradient elution, detection wavelength 254 nm.
- **Mass spectrometry (LC-MS)**: used to identify trace impurity structures.
- **Nuclear magnetic resonance (NMR)**: Verify molecular structure and crystal form.
3. **Stability study**
- Accelerated test (40 degree /75% RH) showed that the API had no significant degradation within 24 months, and the main component content remained above 98%.
#### 5. Application fields and clinical progress
1. **Breast cancer treatment**
- **First-line treatment**: used for adjuvant treatment of postmenopausal ER+/HER2- breast cancer, especially effective for tamoxifen-resistant patients.
- **Metastatic breast cancer**: Combination with CDK4/6 inhibitors (such as palbociclib) can prolong progression-free survival (PFS).
2. **Preventive application**
- Chemoprevention studies in high-risk populations (such as BRCA mutation carriers) showed that exemestane can reduce the incidence of breast cancer by 65%.
3. **Combination therapy exploration**
- **Immunotherapy**: combined with PD-1 inhibitors to regulate the tumor microenvironment (in clinical phase II trials).
- **Targeted drugs**: combined with mTOR inhibitors (everolimus) to overcome endocrine resistance.
#### 6. Market status and prospects
1. **Production and supply**
- **Major manufacturers**: Pfizer (original research), Zhejiang Hisun Pharmaceutical, Jiangsu Hengrui Medicine, etc.
- **Price of API**: About $5000-6000/kg in the international market in 2023, and 20-30% lower in China.
2. **Market demand**
- The global breast cancer drug market is expected to reach $35 billion in 2025, with aromatase inhibitors accounting for more than 30% of the market share.
- Competition in generic drugs intensifies, with Indian and Chinese companies dominating the non-patent market.
3. **Future trends**
- **Development of new dosage forms**: Transdermal patches and long-acting injections reduce oral side effects.
- **Biosimilars**: Optimize the synthesis path through genetic engineering to reduce costs.
#### 7. Summary and outlook
Cim npe nrov: raws powder exemestane(aromasin) treating breast cancer cas:50-41-9, China raws powder exemestane(aromasin) treating breast cancer cas:50-41-9 manufacturers, suppliers, factory
