The main active ingredient of nafarelin tablet is nafarelin. Its chemical structure is modified on the basis of natural GnRH, which improves oral bioavailability and lays a foundation for the clinical application of the tablet dosage form. It boasts advantages such as convenient oral administration, stable plasma drug concentration, and controllable side effects. It avoids the invasiveness and inconvenience of injection formulations, enhances patient medication compliance, and is especially suitable for patients requiring long-term maintenance therapy.
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Nafarelin COA
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| Certificate of Analysis | ||
| Compound name | Nafarelin | |
| Grade | Pharmaceutical grade | |
| CAS No. | 76932-56-4 | |
| Quantity | 23g | |
| Packaging standard | PE bag+Al foil bag | |
| Manufacturer | Shaanxi BLOOM TECH Co., Ltd | |
| Lot No. | 202601090056 | |
| MFG | Jan 9th 2026 | |
| EXP | Jan 8th 2029 | |
| Structure |
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| Item | Enterprise standard | Analysis result |
| Appearance | White or almost white powder | Conformed |
| Water content | ≤5.0% | 0.26% |
| Loss on drying | ≤1.0% | 0.17% |
| Heavy Metals | Pb≤0.5ppm | N.D. |
| As≤0.5ppm | N.D. | |
| Hg≤0.5ppm | N.D. | |
| Cd≤0.5ppm | N.D. | |
| Purity (HPLC) | ≥99.0% | 99.98% |
| Single impurity | <0.8% | 0.45% |
| Total microbial count | ≤750cfu/g | 426 |
| E. Coli | ≤2MPN/g | N.D. |
| Salmonella | N.D. | N.D. |
| Ethanol (by GC) | ≤5000ppm | 618ppm |
| Storage | Store in a sealed, dark, and dry place below 2-8°C | |
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| Chemical Formula | C66H83N17O13 |
| Exact Mass | 1321.64 |
| Molecular Weight | 1322.50 |
| m/z | 1321.64(100.0%), 1322.64(71.4%), 1323.64(25.1%), 1322.63(5.9%), 1324.65(5.8%), 1323.64(4.5%), 1323.64(2.7%), 1324.64(1.9%), 1324.64(1.5%) |
| Elemental Analysis | C,59.94; H,6.33; N,18.01; O,15.73 |
Application in Hirsutism
Hirsutism is an endocrine disorder characterized by excessive, thickened, and darkened body hair in women. Its pathogenesis is closely associated with elevated circulating androgens or increased sensitivity of hair follicles to androgens. It is commonly seen in polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia, ovarian or adrenal tumors, among other conditions. PCOS-related hirsutism accounts for the highest proportion, representing more than 70% of all hirsutism cases. Hirsutism primarily affects the upper lip, chin, chest wall, lower abdomen, medial thighs, and other areas. It not only impairs patients' physical appearance but also causes psychological issues including inferiority complex and anxiety, severely compromising quality of life. Therefore, timely and effective treatment is of great significance.
Nafarelin tablet blocks abnormal hair growth at the source and alleviates hirsutism by continuously inhibiting pituitary gonadotropin secretion, reducing ovarian and adrenal androgen production (including testosterone, androstenedione, etc.), and lowering hair follicle sensitivity to androgens. Clinical studies demonstrate that the therapeutic efficacy of the product for hirsutism exhibits clear dose‑dependence and time‑dependence. Noticeable effects generally emerge after 3–6 months of continuous administration, manifesting as slowed hair growth, finer and lighter‑colored hair, and gradual hair loss in some patients, accompanied by a significant reduction in the Ferriman‑Gallwey score (a commonly used index for evaluating hirsutism severity).
Information source: PubMed (Treatment of hirsutism with a gonadotropin‑releasing hormone agonist (nafarelin); Comparison of a gonadotropin‑releasing hormone agonist and a low dose oral contraceptive given alone or together in the treatment of hirsutism).
Application in Polycystic Ovary Syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age, with a prevalence of approximately 5%–10%. Its core pathological features include hyperandrogenism, insulin resistance, and polycystic ovarian morphology. Major clinical manifestations are oligomenorrhea, amenorrhea, hirsutism, acne, obesity, and infertility. Beyond impairing reproductive health, PCOS increases the long‑term risk of complications such as diabetes and cardiovascular diseases. Current PCOS management is mainly symptomatic, with core goals of regulating endocrine disorders, relieving clinical symptoms, preserving reproductive function, and preventing long‑term complications. With its unique pharmacological effects, it plays an important role in the comprehensive treatment of PCOS.
Regulating endocrine disorders and improving hyperandrogenic symptoms:Hyperandrogenism is a core feature of PCOS and the main cause of hirsutism, acne, and menstrual irregularities. By continuously inhibiting pituitary GnRH receptors, it reduces the secretion of luteinizing hormone (LH) and follicle‑stimulating hormone (FSH), thereby suppressing ovarian androgen synthesis and secretion, lowering serum levels of testosterone, androstenedione, and other androgens, regulating ovarian function, and improving polycystic ovarian morphology. Clinical studies show that after 3 months of it treatment in PCOS patients, serum androgen levels decrease significantly, and symptoms such as hirsutism and acne gradually improve. After 6 months of treatment, polycystic ovarian morphology is alleviated in some patients, with partial recovery of follicular development. In addition, by modulating the secretion rhythm of gonadotropins, it improves ovulatory dysfunction in PCOS patients, laying a foundation for subsequent ovulation induction therapy.
Adjuvant treatment of PCOS‑related infertility:Ovulatory dysfunction is the leading cause of infertility in PCOS patients, affecting 70%–80% of cases. It corrects abnormal ovarian responses by suppressing excessive pituitary gonadotropin secretion, placing the ovaries in a "resting" state and reducing aberrant follicular development, thus restoring normal ovulatory function. In clinical practice, it is often used as a pretreatment for ovulation induction in infertile PCOS patients, especially those with hyperandrogenism and a high risk of ovarian hyperstimulation. Pretreatment significantly improves the success rate of ovulation induction and reduces the risk of ovarian hyperstimulation syndrome. Furthermore, in some patients with luteal phase insufficiency caused by hyperandrogenism, nafarelin tablet can improve luteal function and increase conception rates by regulating hormone levels.
Relieving PCOS‑associated menstrual disorders:Due to abnormal ovarian function and hormonal imbalance, PCOS patients frequently experience oligomenorrhea, amenorrhea, and irregular uterine bleeding. Long‑term menstrual disorders raise the risk of endometrial cancer. It improves and regularizes menstrual cycles by regulating the hypothalamic‑pituitary‑ovarian axis, inhibiting excessive androgen secretion, and restoring the balance between estrogen and progesterone. Clinical data indicate that after 6 months of it treatment, approximately 60%–70% of PCOS patients regain regular menstruation, and the menstrual recovery rate in amenorrheic patients exceeds 50%, effectively lowering the risk of endometrial cancer.
Information source: Pfizer Medical (SYNAREL® Clinical Pharmacology; SYNAREL® Adverse Reactions); GenericPedia (Nafarelin indications, dose, side effects & concise monograph).
1. Raw Material Preparation
Key raw materials for nafarelin synthesis include individual amino acid monomers (pGlu, His, Trp, Ser, Tyr, D‑Nal(2), Leu, Arg, Pro, Gly), solid‑phase carrier resin (commonly benzhydrylamine resin), protecting reagents (for amino, carboxyl, and side‑chain functional groups of amino acids, e.g., tert‑butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz)), coupling reagents (to promote amide bond formation between amino acids, e.g., dicyclohexylcarbodiimide (DCC), 1‑hydroxybenzotriazole (HOBt)), deprotection reagents (e.g., trifluoroacetic acid (TFA), piperidine), and purification reagents (e.g., methanol, acetonitrile, water). All raw materials undergo rigorous purity testing to eliminate interference from impurities. Amino acid monomers are appropriately protected to prevent side reactions during coupling.
2. Activation of Solid‑Phase Carrier Resin
Benzhydrylamine resin is added to a reaction vessel and swelled in dichloromethane (DCM) to fully expand, facilitating subsequent amino acid conjugation. An appropriate amount of deprotection reagent (e.g., TFA) is then added to remove protecting groups from the resin surface, generating free amino groups ready for coupling with the first amino acid. The activated resin is washed sequentially with DCM and N,N‑dimethylformamide (DMF) to remove excess deprotection reagent and impurities, ensuring a pure reaction system.
3. Stepwise Amino Acid Coupling
Amino acid coupling is performed stepwise from the C‑terminus (Gly) to the N‑terminus (pGlu) following nafarelin's amino acid sequence:
pGlu‑His‑Trp‑Ser‑Tyr‑D‑Nal(2)‑Leu‑Arg‑Pro‑Gly‑NH₂. Protected Gly is first introduced and coupled to free amino groups on the activated resin via amide bond formation.
After reaction completion, the resin is washed with DMF and DCM to remove unreacted Gly and coupling reagents. A deprotection reagent is then added to remove the amino‑protecting group of Gly, followed by the next amino acid (Pro), which couples with the free amino group of Gly under coupling reagents.
This process is repeated until all amino acids are sequentially conjugated to the resin, forming the nafarelin peptide backbone.
During coupling, reaction temperature (typically 25–30 °C), reaction time (2–4 hours per amino acid), and pH are tightly controlled to ensure complete conversion and minimize side reactions.
Amino acids with side‑chain functional groups (e.g., His, Ser, Tyr, Arg) are side‑chain protected before coupling to avoid undesired modifications or side reactions. Side‑chain deprotection is performed synchronously with global peptide deprotection after full chain assembly.
4. Peptide Deprotection and Cleavage
Once the full nafarelin peptide chain is assembled, it is cleaved from the resin and globally deprotected. The resin‑bound peptide is treated with a cleavage cocktail (commonly TFA, triisopropylsilane (TIS), and water) at room temperature for 2–3 hours to detach the peptide from the resin and remove all protecting groups, yielding crude nafarelin. After cleavage, the resin is removed by filtration, and the filtrate is poured into excess cold diethyl ether to precipitate crude nafarelin, which is collected by centrifugation.
5. Purification of Crude Product
Crude nafarelin contains unreacted amino acids, residual coupling reagents, and impurity peptides, requiring purification to meet pharmaceutical standards. High‑performance liquid chromatography (HPLC) is the primary purification method, using a reversed‑phase C18 column as the stationary phase and an acetonitrile‑water‑trifluoroacetic acid mixture as the mobile phase under gradient elution to separate nafarelin from impurities. Nafarelin‑containing fractions are collected, concentrated, and lyophilized to obtain high‑purity nafarelin with a purity of ≥98%, complying with medicinal specifications.
6. Salt Formation and Formulation Processing
High‑purity nafarelin is obtained as the free base and is converted to nafarelin acetate to improve water solubility and stability for formulation. Nafarelin is dissolved in methanol and reacted with glacial acetic acid for 1–2 hours with stirring to form nafarelin acetate, which is then concentrated, crystallized, and dried to yield the nafarelin acetate drug substance. The drug substance is blended with suitable excipients (lactose, microcrystalline cellulose, magnesium stearate, etc.) and processed via milling, sieving, granulation, drying, sizing, and tableting to produce nafarelin tablet. Final quality testing is performed, and compliant products are packaged for marketing.
Information source: ChemicalBook (Nafarelin | 76932-56-4), Srivastava V (Peptide-based drug discovery: challenges and new therapeutics), Wikipedia (Nafarelin).
Management of Local Adverse Reactions
Nasal dryness, nasal itching, epistaxis, and pharyngitis are common local reactions and may be relieved by nasal irrigation with normal saline. For severe symptoms, mild nasal lubricants can be used short‑term; strong nasal decongestants should be avoided.
Information source: UK EMC Synarel® 2 mg/ml Nasal Spray Summary of Product Characteristics.
FAQ
Why is Synarel used in IVF?
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In IVF treatment programs, Synarel is used to switch off your own hormone production and prevent a premature luteinising hormone (LH) surge. This allows your doctor to better control the timing of ovulation and egg collection. This medicine is available only on a doctor's prescription.
Does Synarel make you gain weight?
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Synarel may lead to enlargement of the ovaries due to excess egg production (OHSS – Ovarian Hyperstimulation Syndrome). This can lead to pain in the pelvis, stomach or calf, swelling or feeling bloated, passing less urine, difficulty in breathing or an increase in weight.
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