| HS Code | 383348 |
| Product Name | Gonadorelin Acetate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Api | Gonadorelin Acetate |
| Pharma Grade | Pharma Grade |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Route Of Administration | Oral and Injectable |
| Chemical Name | 5-oxo-Pro-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 acetate salt |
| Cas Number | 52699-48-6 |
| Molecular Formula | C55H76N16O12 · C2H4O2 |
| Molecular Weight | 1271.43 g/mol |
| Appearance | White to off-white crystalline powder |
| Solubility | Freely soluble in water; sparingly soluble in ethanol |
| Assay | Typically ≥98.0% (on dried basis) |
| Storage | Store at 2-8°C, protected from light and moisture |
| Application | Used as an active pharmaceutical ingredient in formulations for hormone regulation |
As an accredited Gonadorelin Acetate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in 25kg fiber drums, double polyethylene-lined, sealed for pharmaceutical use. Suitable for tablets, capsules, granules, and oral/injectable formulations. |
| Container Loading (20′ FCL) | 20′ FCL container loading of Gonadorelin Acetate Pharma Grade API, packaged for tablet, capsule, granule, and injectable formulations. |
| Shipping | Ship globally in temperature-controlled, sealed containers to maintain stability. Shipments include tamper-evident packaging, compliant labeling, and full documentation for pharmaceutical raw materials. Delivery options cover air, sea, and express courier, with cold-chain monitoring available. Ensure import permits and local regulatory requirements are confirmed before dispatch. |
| Storage | Store Gonadorelin Acetate Pharma Grade API in tightly sealed, light-resistant containers, in a cool, dry place below 25°C. Protect from moisture, direct sunlight, heat, and humidity. Refrigeration at 2–8°C is recommended for prolonged stability; do not freeze. For tablet, capsule, granule, oral, and injectable formulations, follow pharmacopeial handling requirements and keep away from incompatible substances. |
| Shelf Life | Shelf life is typically 24 months when stored under recommended conditions, protected from light, moisture, and heat in sealed packaging. |
In diagnostic protocols, gonadorelin acetate is filled as a sterile lyophilised cake at a single-dose strength of 100 µg per vial. The bulk formulation is compounded at 2–8°C in Water for Injection, with mannitol added as a crystallising bulking agent at API-to-excipient ratios between 1:20 and 1:100 w/w; glycine may substitute for mannitol when a more amorphous cake is required for faster reconstitution. The aqueous solution is pH-adjusted with dilute acetic acid or sodium hydroxide to a target range of 4.5–6.0, then filtered through a 0.22 µm polyethersulfone membrane into Type I borosilicate glass vials. Lyophilisation is performed with a chamber pressure below 0.2 mbar during primary drying, and shelf temperature ramps at 0.3°C/min to a target below the collapse temperature identified by freeze-drying microscopy; this avoids microcollapse and preserves cake integrity. The finished product is closed under vacuum or nitrogen and tested for moisture according to Ph. Eur. 2.5.12, particulate matter according to USP <788>, and bacterial endotoxins according to Ph. Eur. 2.6.14. Reconstitution with 1.0 mL of sodium chloride 9 mg/mL produces an injection for intravenous bolus administration; absent antimicrobial preservative, the reconstituted solution is assigned a short in-use holding period at 2–8°C for a clinically justified interval, and residual liquid is discarded after single-patient use.
For pulsatile restoration of endogenous gonadotropin secretion in hypogonadotropic hypogonadism, the acetate salt is prepared as a subcutaneous infusion solution administered by an ambulatory syringe pump. The prescribed pulse dose is drawn from a reservoir concentration commonly 100 µg/mL, with individual pulses reported between 5 µg and 25 µg at intervals of 60–120 min. Because the native decapeptide adsorbs to polyvinyl chloride, the fluid path is specified in high-density polyethylene or Type I borosilicate glass reservoirs, and low-protein-binding extension sets are used to reduce surface loss. The compounding sequence dilutes the API in sterile 0.9% sodium chloride under ISO grade 5 laminar airflow; terminal sterilisation is excluded because the peptide degrades at steam sterilisation temperatures. Sterile filtration through a 0.22 µm low-protein-binding polyvinylidene fluoride membrane is performed before filling into cassette syringes. The terminal product is a single-patient infusion cartridge protected from light and stored at 2–8°C; in-use ambulatory stability is limited to 24 h at body temperature because aqueous oxidation of the tryptophan residue and peptide hydrolysis accelerate as temperature increases and the external infusion line is outside the controlled cold chain. Compliance with EU GMP Annex 1 and USP <797> governs aseptic compounding; chemical stability is confirmed by a stability-indicating high-performance liquid chromatographic method with peak purity evaluation under ICH Q2(R1).
Direct compression of gonadorelin acetate into oral tablets is constrained primarily by dose uniformity and segregation risk, not by compressibility. When a 0.5 mg or 1.0 mg tablet is specified for gastrointestinal stability or preclinical oral dosing, the API is first passed through a 150 µm sieve and its particle size distribution is recorded by laser diffraction according to Ph. Eur. 2.9.31. A geometric dilution sequence is executed in 1:1 increments into microcrystalline cellulose and lactose monohydrate, followed by addition of crospovidone at 4–6% w/w and magnesium stearate at 0.25–1.0% w/w. Lubrication is limited to 3–5 min because longer blending of the low-dose peptide blend increases segregation potential and can produce shear-induced agglomerates. Tablets are compressed on a rotary press fitted with 7 mm round biconcave tooling; main compression force is adjusted to produce a hardness of 5–10 kp, and friability is tested according to Ph. Eur. 2.9.7. Content uniformity is evaluated on 10 units according to Ph. Eur. 2.9.40 or USP <905>, with an acceptance value not exceeding 15.0. Because the native peptide is rapidly degraded in gastric and intestinal fluid and complete oral absorption is not established, the terminal tablet is an experimental oral solid unit rather than a substitute for injectable therapy. Published data for this specific configuration are limited; operating conditions must be verified against a stability-indicating HPLC assay.
| Oral solid route | Critical unit operation | Compendial test method | In-process limit |
|---|---|---|---|
| Direct compression | API pre-sieve and final blend lubrication | Ph. Eur. 2.9.40 | AV ≤ 15.0 for 10 units |
| Wet granulation | Drying endpoint and granule moisture | Ph. Eur. 2.2.32 | LOD ≤ 2.0%; inlet air ≤ 40°C |
| Capsule filling | Flow and compressibility of low-dose blend | Ph. Eur. 2.9.36 | Carr index ≤ 25% |
In granule manufacturing for capsule filling, the aqueous solubility of gonadorelin acetate is exploited in a low-shear planetary mixer, but the wet mass is highly sensitive to binder addition and drying temperature. The API is dissolved or dispersed in purified water before blending with lactose monohydrate, maize starch, and microcrystalline cellulose; because gonadorelin is a peptide, the granulation fluid is held at 2–8°C before use and the wet mass is discharged within 20 min to limit prolonged moisture exposure. Drying in a fluid-bed unit is conducted with inlet air temperature not exceeding 40°C; product temperature is monitored by a probe and the endpoint is set at loss-on-drying not more than 2.0% by Ph. Eur. 2.2.32. The dried granules are passed through a 0.8 mm screen and filled into hard gelatin or hypromellose capsules using a dosator or tamping-pin machine. Terminal product is an oral capsule containing 100 µg to 1 mg of gonadorelin acetate, but this remains a formulation development intermediate rather than a licensed finished product because oral bioavailability is low and the intact peptide is metabolised in the gastrointestinal lumen. Granule mass uniformity is tested according to Ph. Eur. 2.9.5, and dissolution is assessed only for enteric-coated configurations because unprotected oral granules release prematurely at gastric pH.
Enteric coating of gonadorelin-loaded granules is specified only when the dosage form must bypass gastric acid dissolution and expose the peptide to the higher pH environment of the small intestine. The coating polymer is a methacrylic acid-ethyl acrylate copolymer dispersion, applied in a fluid-bed processor fitted with a Wurster column and bottom-spray nozzle; coating weight gain is held between 15% and 25% w/w based on uncoated granule mass, with triethyl citrate added as plasticiser at 10–20% w/w of polymer solids. Inlet air temperature during coating is maintained below 40°C to limit oxidative degradation of the tryptophan residue, and the product is cured at 30–35°C for 30 min to complete film coalescence. Enteric-coated multiparticulates are filled into hard capsules or compressed into tablets after blending with an external phase of microcrystalline cellulose and sodium starch glycolate. The enteric performance is tested according to USP <711>: acid-stage exposure to 0.1 N hydrochloric acid for 2 h must show not more than 10% released, followed by buffer stage at pH 6.8 with not less than 80% released within 45 min. This multiparticulate route does not solve the permeability barrier of the intact decapeptide; pancreatic peptidases in the small intestine continue to degrade gonadorelin, and systemic exposure after oral administration remains low unless absorption enhancement is integrated. The terminal product is therefore an investigational oral capsule used to evaluate oral peptide delivery rather than a marketed oral dosage form.
Ready-to-use injectable solutions of gonadorelin acetate are prepared for assisted reproduction clinics when syringe-based subcutaneous or intravenous delivery is required. Sterile filtration of a 100 µg/mL bulk solution through a 0.22 µm membrane can reduce peptide recovery if the filter surface area is large relative to the batch volume; adsorptive loss is evaluated with low-protein-binding polyvinylidene fluoride or polyethersulfone membranes. A filter challenge study according to PDA Technical Report 26 compares pre-filtration and post-filtration peptide concentration by HPLC; if post-filtration recovery falls below 95%, the filter is pre-rinsed with the formulation vehicle or the membrane area is reduced. The aseptic filling operation is performed in an ISO 5 environment under EU GMP Annex 1, and the final container is Type I glass or cyclic olefin polymer with nitrogen overlay to reduce oxidative degradation. The terminal product is a cartridge or vial solution at 10–100 µg/mL, stored at 2–8°C and protected from light; because no preservative is present, it is labelled for single-patient use and the administration line is primed with 0.5 mL of solution to account for void volume. Particulate matter is controlled to USP <788> limits for small-volume injectable preparations, and bacterial endotoxin limits are aligned with Ph. Eur. 2.6.14. The operational boundary is strict: once warmed to ambient temperature, the peptide solution should not be refrozen, and repeated needle punctures of a vial are avoided because stopper coring raises particulate counts above compendial thresholds.
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Gonadorelin acetate is the acetate salt of a synthetic decapeptide corresponding to the native mammalian gonadotrophin-releasing hormone sequence pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. The API is manufactured by Fmoc/t-Bu solid-phase peptide synthesis on a Rink amide resin, followed by cleavage, preparative reversed-phase HPLC purification, counterion exchange to acetate, and lyophilization. The resulting white to off-white powder is supplied in two processing grades: a solid-dose grade for tablet, capsule, and granule operations, and an injectable grade with reduced bioburden and bacterial endotoxin controls for aseptic processing. The injectable route is the only clinically established route for the native sequence; oral solid-dose applications are investigational and require formulation-specific stability and permeability justification. The key differentiation from other gonadotrophin-releasing hormone analogues is the absence of substitutions at position 6 and the C-terminus, which preserves the native sequence but also retains high susceptibility to proteolytic degradation.
In solid-dose operations, the oral-grade material is typically micronized and controlled for particle size to support blend uniformity in low-dose tablets or capsules. For injectable operations, the same chemical entity is supplied in depyrogenated containers with a defined endotoxin limit. Because the native peptide is rapidly degraded by gastrointestinal peptidases and exhibits low mucosal permeability, oral tablet or capsule products are not pharmacokinetically interchangeable with injectable products. Published data for a commercial oral gonadorelin tablet configuration is limited; therefore the oral grade should be treated as a starting material for development rather than an established formulation platform.
The free-base molecular formula is C55H75N17O13, corresponding to a molecular mass of 1182.3 g/mol. The acetate salt is assigned CAS 52699-48-4. Identity is confirmed by high-resolution mass spectrometry and sequence-specific MS/MS fragmentation, with amino acid analysis used as an orthogonal method for peptide content. The compendial alignment is evaluated against the current USP Gonadorelin Acetate monograph and the corresponding Ph. Eur. monograph; assay is commonly expressed as 95.0–105.0% on an anhydrous, solvent-free basis. Acetate counterion is controlled because it contributes to the assay calculation and may affect lyophilized cake appearance, reconstitution time, and pH.
The quality targets for oral and injectable grades differ mainly in microbial and particulate control. Table 1 gives a representative matrix based on current compendial and ICH guidance. Limits shown are operational control points and do not replace the current monograph text or regional pharmacopeial requirements.
| Attribute | Reference method | Oral solid-dose grade | Injectable grade |
|---|---|---|---|
| Appearance | Visual inspection | White to off-white lyophilized powder | |
| Identification | HPLC retention time; MS/MS sequence; AAA | Consistent with reference material | |
| Assay by HPLC | USP, Ph. Eur. | 95.0–105.0% on dried basis | |
| Chromatographic purity | USP | ≥98.0% | ≥98.5% |
| Largest unspecified impurity | USP | ≤0.5% | ≤0.2% |
| Total impurities | USP | ≤2.0% | ≤1.5% |
| Acetate content | Ion chromatography | 5.0–12.0% w/w | |
| Water content | Ph. Eur. 2.5.12, USP <921> | ≤7.0% | ≤5.0% |
| Residual acetonitrile | ICH Q3C | ≤410 ppm | |
| Residual methanol | ICH Q3C | ≤3000 ppm | |
| Trifluoroacetate | Ion chromatography | ≤0.1% w/w as TFA | |
| Bacterial endotoxins | Ph. Eur. 2.6.14, USP <85> | Not specified | ≤0.5 EU/mg |
| Microbial enumeration | Ph. Eur. 2.6.12/2.6.13 | ≤100 CFU/g | ≤10 CFU/g |
| Elemental impurities | ICH Q3D | Conforms after risk assessment; Class 1 and 2A elements controlled | |
The native sequence is a substrate for luminal and brush-border peptidases. Aminopeptidase attack is partially reduced by the pyroglutamyl N-terminus, but the remaining peptide bonds are susceptible to cleavage by chymotrypsin and trypsin in the small intestine. Gastric acid protection alone does not solve the delivery challenge because the major degradation compartment is post-gastric. Permeability across Caco-2 monolayers is low without a permeation enhancer because the peptide has a molecular mass above 1.1 kDa, a polar surface area consistent with low passive diffusion, and ionizable arginine and histidine residues that restrict transcellular transport. Oral tablet, capsule, and granule prototypes therefore require enteric protection, protease inhibition, and likely a permeation enhancer; however, the enhancer must not irreversibly disrupt intestinal epithelium. Published data for a commercial oral gonadorelin tablet configuration is limited, and bioequivalence to injectable gonadorelin cannot be assumed.
For low-dose dry blends, geometric dilution with lactose monohydrate or mannitol is used to achieve content uniformity. The API particle size is controlled by laser diffraction; an operational target of D90 ≤75 µm is typical for low-dose peptide tablets, but requirements depend on the final dose. Direct compression is preferred over wet granulation with aqueous binders because hydration accelerates peptide aggregation and can cause sticking to tooling. Dry granulation by slugging or roller compaction can be used if the blend exhibits poor flow, but the compaction force must be limited to avoid shear-induced amorphization of the peptide.
The injectable grade is dissolved in Water for Injection, sterile-filtered through a 0.22 µm polyethersulfone or PVDF membrane, and aseptically filled. Chemical stability is pH-dependent; the solution is commonly buffered in the range 4.0–5.5. Nitrogen sparging and light-protected processing reduce oxidation of the tryptophan residue. Lyophilized formulations generally include mannitol or trehalose as bulking and cryoprotective excipients. The collapse temperature is determined by freeze-drying microscopy, and primary drying is conducted below the collapse temperature with a margin of 2–3 °C. Residual moisture in the finished lyophilized cake must be validated, and the reconstituted solution is tested for subvisible particulate matter according to Ph. Eur. 2.9.19 and USP <788>.
The bacterial endotoxin limit for the bulk API is derived from the maximum intended dose. For an intravenous diagnostic bolus of 100 µg, a bulk API limit of 0.5 EU/mg yields 0.05 EU per dose, which is far below the 5 EU/kg threshold defined in USP <85> for a 70 kg patient. Sterility of the finished injectable is not assured by the API alone; the API is bioburden controlled, and terminal sterilization is generally not appropriate for peptide solutions because autoclaving causes thermal and hydrolytic degradation, while gamma irradiation can induce free-radical damage to the peptide side chains.
The primary structural difference is that gonadorelin acetate contains the native mammalian sequence. Leuprolide contains a D-leucine substitution at position 6 and a C-terminal ethylamide, triptorelin contains a D-tryptophan at position 6, and goserelin contains a D-serine(t-Bu) at position 6 with an azaglycine at position 10. These substitutions reduce enzymatic cleavage and prolong receptor occupancy. The consequence is that gonadorelin acetate is used clinically as a diagnostic agent or for pulsatile subcutaneous infusion, while the synthetic analogues are used for continuous receptor down-regulation in sex-steroid-dependent conditions. In pharmaceutical processing, the analogues are typically formulated as depot injection or implant products with biodegradable polymeric excipients, whereas gonadorelin acetate is supplied as a simple lyophilized injection or compounded solution.
| Attribute | Gonadorelin acetate | Leuprolide acetate | Triptorelin acetate | Goserelin acetate |
|---|---|---|---|---|
| Sequence class | Native GnRH | Synthetic superagonist | Synthetic superagonist | Synthetic superagonist |
| Position-6 substitution | None | D-Leu | D-Trp | D-Ser(t-Bu) |
| C-terminal modification | None; Gly-NH2 | Pro-NHEt | None; Gly-NH2 | Azagly-NH2 |
| Enzymatic susceptibility | High | Reduced | Reduced | Reduced |
| Typical finished dosage form | Injection or pulsatile infusion | Depot injection or implant | Depot injection | Implant |
| Primary pharmacological use | Diagnostic evaluation of pituitary LH/FSH reserve | Continuous down-regulation | Continuous down-regulation | Continuous down-regulation |
The pharma grade designation differs from research-grade gonadorelin acetate through manufacturing under a quality system aligned with ICH Q7, full impurity characterization, and controls for residual solvents, elemental impurities, and microbial contamination. Research-grade material is not suitable for tablet or injectable manufacture because it typically lacks the validated analytical methods, stability data, and supply chain traceability required for regulatory submission. The oral-grade material differs from injectable-grade material only in particle size, microbial limits, endotoxin specification, and packaging; the chemical entity and impurity profile are identical because both are prepared from the same purified peptide batch. This distinction is operational, not structural, and should be reflected in the regulatory file by separate specifications for the final route of administration. The material should be stored at -20 °C for long-term stability, protected from light, and equilibrated to room temperature before opening to prevent moisture condensation on the lyophilized powder.
