CAS 118072-93-8 | Zoledronic Acid

✅ Pharmaceutical API

1. Osteoporosis Management- Postmenopausal osteoporosis (PMOP) in women: Reduces the risk of vertebral, non-vertebral, and hip fractures; improves lumbar spine and hip BMD.- Glucocorticoid-induced osteoporosis (GIOP) in adults: Prevents bone loss caused by long-term glucocorticoid use (≥7.5 mg/day prednisone equivalent).- Male osteoporosis: Increases BMD and reduces fracture risk in hypogonadal or age-related male osteoporosis patients.

2. Tumor-related Bone Complications- Treatment of osteolytic bone metastases from solid tumors (breast, prostate, lung cancer) and multiple myeloma: Relieves bone pain, reduces the risk of skeletal-related events (SREs) including pathological fractures, spinal cord compression, and the need for bone radiotherapy/surgery.- Treatment of hypercalcemia of malignancy (HCM): Rapidly lowers serum calcium levels by inhibiting bone resorption.

3. Rare Bone Diseases- Paget's disease of bone: Normalizes bone turnover markers and relieves bone pain in patients with active disease.

▶ API Raw Material Packaging

▸ Lab/Research Grade: Sealed amber glass vials with Teflon-lined screw caps, specifications: 1 g, 5 g, 10 g, 25 g; purity ≥99.5%, vacuum-sealed to prevent moisture absorption and oxidation.

▸ Industrial/Pharmaceutical Grade: HDPE plastic drums or fiber drums with double polyethylene (PE) inner liners (moisture-proof and oxygen-barrier), specifications: 1 kg, 5 kg, 25 kg, 50 kg; drum labels include CAS number, batch number, purity, net weight, storage conditions, GMP certification, and hazard warnings (avoid skin/eye contact, corrosive to mucous membranes).

▸ Customized Export Packaging: 10 g/50 g/100 g aluminum foil vacuum bags for small-batch shipments; labeled with ICH Q7 standards and international transportation marks (classified as non-hazardous chemical for export, but marked as corrosive).

▶ Finished Product Packaging▸ Injection: Single-dose glass vials (4 mg/vial) packaged in blister packs with rubber stoppers and aluminum crimp seals; each box contains 1 vial plus a vial of sterile water for injection (for reconstitution) and a disposable syringe.▸ Oral tablets: HDPE bottles with child-resistant caps (30 tablets/bottle for 5 mg dosage; 4 tablets/bottle for 15 mg once-monthly dosage); blister packs available for clinical use.

▶ Storage & Shelf Life Requirements

API storage:

2–8°C cold storage, protected from light, dry and well-ventilated environment; avoid contact with strong acids, bases, and metal ions.

Transportation:

Cold chain transportation for API and injection products (insulated containers with temperature monitors); normal temperature transportation for oral tablets with moisture-proof packaging.

Raw Materials:

Imidazole-1-acetic acid hydrochloride, phosphorus oxychloride (POCl₃), phosphoric acid, sodium hydroxide

Steps (5-step scalable synthesis, mild conditions, low impurity generation)

1. Esterification: React imidazole-1-acetic acid hydrochloride with methanol under concentrated sulfuric acid catalysis at 60–70°C to obtain methyl imidazole-1-acetate (intermediate 1).

2. Phosphorylation: Add intermediate 1 dropwise to a mixture of POCl₃ and phosphoric acid (molar ratio 1:3:2) at 0–5°C, then heat to 80–90°C for 4–6 hours to carry out the Arbuzov reaction; obtain 1-(diethoxyphosphoryl)ethyl-1H-imidazole (intermediate 2).

3. Hydrolysis & Decarboxylation: Add intermediate 2 to a 20% sodium hydroxide solution, heat to reflux for 2–3 hours to hydrolyze the ester group and remove the ethyl protecting group; adjust pH to 1–2 with concentrated hydrochloric acid to induce decarboxylation, forming 1-(phosphonomethyl)imidazole (intermediate 3).

4. Bisphosphonation: React intermediate 3 with formaldehyde solution and phosphorous acid in the presence of concentrated hydrochloric acid at 90–100°C for 8–10 hours; the methylene group connects to the phosphorus atom to form the bisphosphonate structure, yielding crude zoledronic acid.

5. Purification & Crystallization: Dissolve the crude product in water, decolorize with activated carbon, filter, and adjust the filtrate pH to 4–5 with sodium hydroxide; cool to 0–5°C for crystallization, filter, wash with cold water, and dry under vacuum at 50–60°C to obtain zoledronic acid white crystalline powder.