Description

Technical Parameters

Introduction

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product-1400-1400

Products Description

#### **1. Overview**

Sildenafil Citrate is the first oral phosphodiesterase-5 (PDE-5) inhibitor developed by Pfizer. It was approved by the FDA in 1998 for the treatment of male erectile dysfunction (ED). Its API is a white to off-white crystalline powder with high selectivity and long-lasting effect, becoming a milestone in the field of ED treatment. In addition, its derivatives (such as Revatio®) are also used in the treatment of pulmonary arterial hypertension (PAH).

#### **2. Chemical properties and CAS number**

1. **Chemical structure**

- Molecular formula: C₂₂H₃₀N₆O₄S·C₆H₈O₇

- Molecular weight: 666.7 g/mol

- Structural features: Contains pyrazolopyrimidinone core and sulfonyl group, and the citrate form enhances water solubility.

2. **CAS number**

- Sildenafil base: 171599-83-0

- Sildenafil citrate: 139755-83-4

3. **Physical and chemical properties**

- Solubility: slightly soluble in water (3.5 mg/mL, 25℃), easily soluble in DMSO and methanol.

- Melting point: 188-190℃ (decomposition temperature).

- Stability: stored in dark, pH sensitive (optimum pH 3-5).

#### **3. Classification and advantages analysis**

According to the application and preparation form, sildenafil API can be divided into the following categories:

##### **1. Classification by indication**

- **API for ED treatment**

- **Advantages**: selective inhibition of PDE-5, enhancement of NO-mediated vasodilation, oral bioavailability of about 40%.

- **Dosage**: Typical formulation is 25-100 mg tablet, effective in 30-60 minutes.

- **API for PAH treatment (Revatio®)**

- **Advantages**: Reduce pulmonary artery pressure and improve patient exercise capacity by inhibiting pulmonary vascular PDE-5.

- **Dosage**: 20 mg tablet, 3 times a day; or injection dosage form.

##### **2. Classification by formulation process**

- **Ordinary tablet API**

- Process requirements: Particle size control (D90＜50 μm) to improve dissolution.

- **Orally disintegrating tablet/immediate release dosage form API**

- Advantages: No need to take with water, suitable for patients with dysphagia.

- **Nanocrystalline formulation API**

- Technical highlights: Improve bioavailability and reduce dose-dependent side effects.

##### **3. Classification by purity level**

- **Pharmacopoeia grade (USP/EP/ChJP)**

- Standard: Purity ≥ 99.0%, single impurity < 0.1%.

- **Customized synthesis grade**

- Application: Scientific research or special formulation development, deuterated markers (such as D3-Sildenafil) can be customized.

#### **4. Synthesis process and technical difficulties**

1. **Chemical synthesis route**

- **Mainstream process**: 2-pentanone is used as the starting material, and it is synthesized through 7 steps of condensation, cyclization, sulfonation, etc.

- **Key intermediates**: Pyrazolopyrimidinone skeleton (step 3), sulfonamide group introduction (step 5).

2. **Purification technology**

- Crystallization optimization: Anti-solvent crystallization method is used to control the crystal form (mainly polymorph I).

- Chromatographic purification: used to remove chiral impurities (such as R-isomer).

3. **Green chemistry improvement**

- Solid phase synthesis: reduce the use of organic solvents and increase the yield to more than 75%.

- Enzyme catalysis: replace highly toxic sulfonation reagents and reduce environmental load.

#### **5. Quality control and pharmacopoeia standards**

1. **Key test items**

- **Content determination**: HPLC method (USP standard: 98.0%-102.0%).

- **Impurity spectrum**: including 8 known impurities such as N-demethylated products and epoxides.

- **Dissolution**: paddle method (900 mL pH 4.5 buffer, 30 minutes dissolution> 80%).

2. **Stability study**

- Accelerated test (40℃/75% RH, 6 months): total impurity growth ≤0.5%.

- Photostability: must comply with ICH Q1B guidelines.

#### **6. Global market and regulatory environment**

- **Major manufacturers**: Pfizer (original research), India's Dr. Reddy's, China Guangyao Group, etc.

- **Regulatory requirements**: Must comply with cGMP, ICH Q7, China must pass NMPA on-site inspection.

- **Patent situation**: Core patents have expired, and global generic drugs account for more than 70%.

- **Price trend**: API price is about $2000-2500/kg (2023 data).

#### **7. Future development trends**

1. **Development of new dosage forms**: transdermal patches, long-acting injections (such as PLGA microspheres).

2. **Indication expansion**: Preclinical studies of Alzheimer's disease and high-altitude pulmonary edema.

3. **Process innovation**: Continuous flow chemistry improves synthesis efficiency.

4. **Biosimilars**: Exploration of engineering bacteria synthesis pathways based on CRISPR technology.

#### **8. Storage and transportation specifications**

- **Conditions**: light-proof, airtight, 20-25℃ (long-term); 2-8℃ (better for long-term storage).

- **Packaging**: double-layer aluminum foil bag filled with nitrogen, plus moisture-proof agent.

- **Transportation**: cold chain (2-8℃) is required, avoid severe vibration.

#### **Conclusion**

The technical barriers of sildenafil API are high, but its broad application prospects drive the continuous innovation of synthesis process and formulation technology. With the development of precision medicine, its potential in personalized treatment will be further released.