| HS Code | 710671 |
| Product Name | Sodium Phenylacetate |
| Synonyms | Sodium 2-phenylacetate; Phenylacetic acid sodium salt |
| Cas Number | 114-70-5 |
| Einecs Number | 204-045-3 |
| Iupac Name | Sodium 2-phenylacetate |
| Molecular Formula | C8H7NaO2 |
| Molecular Weight | 158.13 g/mol |
| Appearance | White to off-white crystalline powder |
| Color | White to off-white |
| Form | Crystalline powder |
| Odor | Odorless or slight characteristic odor |
| Melting Point | >300 °C (decomposes) |
| Vapor Pressure | Negligible at 20 °C |
| Solubility In Water | Freely soluble in water |
| Solubility In Ethanol | Slightly soluble in ethanol |
| Ph | 7.0 to 9.0 (1% aqueous solution) |
| Pka Conjugate Acid | 4.31 |
| Assay | >=98.0% |
| Water Content | <=1.0% |
| Hygroscopicity | May be hygroscopic; protect from moisture |
| Stability | Stable under normal storage conditions |
| Incompatibilities | Strong oxidizing agents |
| Storage Conditions | Store in a cool, dry, well-ventilated area away from moisture and heat |
| Shelf Life | 24 months when stored properly |
As an accredited Sodium Phenylacetate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Sodium Phenylacetate is packaged in 25 kg moisture-resistant fiber drums with double polyethylene liners and secure chemical labels. |
| Container Loading (20′ FCL) | Container Loading (20′ FCL): Sodium Phenylacetate in sealed drums, palletized and secured in a 20′ FCL dry container with chemical labels. |
| Shipping | Sodium Phenylacetate is generally shipped as a nonhazardous, hygroscopic solid in sealed, labeled containers. Transport at ambient temperature, protecting it from moisture, heat, and direct sunlight. Keep containers closed, segregate from oxidizers, and follow DOT/IATA/IMDG regulations plus the SDS. Verify classification for solutions or mixtures. |
| Storage | Store Sodium Phenylacetate in a cool, dry, well-ventilated area at controlled room temperature in a tightly closed, labeled container. Protect from moisture, heat, and direct sunlight. Keep away from acids, strong oxidizers, and other incompatible materials. Use appropriate secondary containment to prevent spills. Ensure containers are clearly marked with hazard information. Follow local regulations and the safety data sheet. |
| Shelf Life | Sodium Phenylacetate shelf life: typically 2–3 years when stored tightly sealed, dry, at room temperature, protected from moisture and light. |
Sodium phenylacetate, CAS 114-70-5, functions as a water-soluble phenylacetate anion source in submerged cultivation of Penicillium chrysogenum for benzylpenicillin. In production-scale fed-batch fermentation, the free acid is often replaced by the sodium salt to prevent localized pH depression and to reduce transient mycelial contact toxicity when the precursor is pulsed into the broth. The salt is dissolved in deionized water to form a feed concentrate in the 10–20 wt% range and is metered through a dedicated positive-displacement pump line separate from the carbohydrate feed. Fed-batch precursor addition begins after the rapid trophophase, when biomass-specific oxygen uptake has stabilized, and the residual free phenylacetic acid concentration is maintained below the strain-specific inhibitory threshold of ≤1 g/L. Above that range, oxidative phosphorylation uncoupling, reduced specific penicillin formation, and increased precursor carry-over into the extraction stream are recognized failure modes on industrial lines.
Commercial stirred-tank bioreactors used for this application have working volumes from 40,000 L to 200,000 L, aspect ratios from 2:1 to 3:1, and multiple Rushton or hydrofoil impellers. The phenylacetate feed nozzle is submerged to limit aerosol loss, and the feed is delivered as short pulses rather than as a continuous unregulated stream where online HPLC feedback is unavailable. Off-gas mass spectrometry and periodic residual precursor assay are used to trim the feed rate; overfeed causes transient free acid accumulation, while underfeed limits the acylation of the β-lactam side chain and depresses final titer. The process window is narrow because the precursor simultaneously serves as the side-chain donor and as a potential inhibitory organic acid.
Downstream, the fermentation broth is cooled, acidified to pH 2.0–2.5, and extracted with butyl acetate. Benzylpenicillin is recovered as the potassium or sodium salt, and residual phenylacetic acid is separated in the aqueous raffinate. The final antibiotic salt must meet the related-substance and assay limits of the USP and Ph. Eur. monographs for benzylpenicillin; residual phenylacetic acid and phenylacetamide are controlled as impurities because they are carried into the solvent extraction phase at low levels.
The combination of sodium phenylacetate and sodium benzoate is used as a parenteral nitrogen-scavenging therapy for hyperammonemia in urea cycle disorders. The sterile concentrate contains 100 mg/mL sodium phenylacetate and 100 mg/mL sodium benzoate, with pH adjusted to 6.0–8.0. Sodium phenylacetate is activated in the liver to phenylacetyl-CoA, conjugated with glutamine to form phenylacetylglutamine, and excreted by the kidney. Sodium benzoate provides a parallel nitrogen removal route through glycine conjugation to hippurate. The two routes operate independently of the defective urea cycle and are therefore clinically relevant when carbamoyl phosphate synthetase, ornithine transcarbamylase, or later cycle enzymes are deficient.
Before intravenous administration, the concentrate is diluted in 10% dextrose injection USP. The undiluted solution is hyperosmotic, and admixture with other drugs, blood products, or incompatible electrolyte solutions is not recommended because of precipitation and osmotic injury risk. Each milliliter of the concentrate delivers approximately 30 mg of sodium; this sodium load imposes an operational boundary in patients with congestive heart failure, severe renal impairment, hypernatremia, or fluid restriction. Infusion requires a dedicated line, and extravasation is a recognized hazard because the high osmolality can cause tissue necrosis. Weight-based dosing is specified in the FDA-approved labeling; the dose is adjusted when renal excretion of phenylacetylglutamine is impaired.
| Parameter | Specification or test method |
|---|---|
| Sodium phenylacetate strength | 100 mg/mL |
| Sodium benzoate strength | 100 mg/mL |
| Diluent | 10% dextrose injection USP |
| pH range | 6.0–8.0 |
| Sterility | USP <71> |
| Bacterial endotoxins | USP <85> |
| Particulate matter | USP <788> |
| Elemental impurities | ICH Q3D threshold limits |
During prolonged infusion, serum ammonia, plasma amino acids, sodium, potassium, and anion gap are monitored. Phenylacetylglutamine clearance falls with renal impairment, and the resulting metabolite accumulation can intensify the osmotic load. The product is not interchangeable with oral sodium phenylbutyrate because the metabolic activation steps and sodium loads differ. Compliance for the finished injection includes stability under the labeled storage condition, pH, particulate matter, and endotoxin limits shown above.
Methyl and ethyl phenylacetate possess a sweet, honey-like odor with rosy undertones and are used in fragrance compositions; sodium phenylacetate serves as the industrial phenylacetate anion source when the free acid is not directly charged. In a glass-lined reactor, an aqueous solution of sodium phenylacetate is acidified with sulfuric acid using a 2:1 molar ratio of carboxylate salt to sulfuric acid, yielding free phenylacetic acid and sodium sulfate. Because phenylacetic acid melts at 76 °C, the liberated acid can be kept molten or dissolved in the alcohol reactant. Methanol or ethanol is then charged with an acid catalyst, typically p-toluenesulfonic acid at 0.5–2.0 wt% of the organic phase, and the mixture is heated under reflux with water removal through a Dean-Stark trap or distillation column. The crude ester is washed with dilute sodium carbonate solution to remove residual acid, dried, and vacuum distilled at 2–5 kPa absolute pressure. Final product specifications include ester content by GC at ≥99% and acid value ≤1.0 mg KOH/g.
The same salt can be converted to benzyl phenylacetate through reaction with benzyl chloride after acidification or through phase-transfer displacement; benzyl chloride handling requires closed feed systems and scrubbing of hydrogen chloride off-gas. Fragrance-grade phenylacetate esters are evaluated under the IFRA 49th Amendment and RIFM safety assessment endpoints for dermal sensitization, phototoxicity, and systemic exposure. Esterification from the sodium salt avoids the dusting and molten handling of free phenylacetic acid and allows automated liquid charging into closed reactors.
For phenylacetamide synthesis, sodium phenylacetate is first acidified to phenylacetic acid and then converted to the ammonium salt before thermal dehydration. Urea or ammonium carbonate is charged at 1.1–1.3 mol per mole of phenylacetic acid in a glass-lined or stainless steel reactor fitted with an overhead condenser and an ammonia scrubber. Dehydration proceeds with evolution of carbon dioxide and ammonia; the mixture is heated until the melt solidifies on cooling. The crude phenylacetamide is recrystallized from water or ethanol/water and controlled for melting point at 157–158 °C and residual free acid below 0.5 wt%. The amide is used as an intermediate in pharmaceutical acylation routes, dye synthesis, and polymer stabilizer chemistry; downstream chloromethylation or condensation reactions require low water and low free acid to avoid side-product formation. The sodium sulfate generated during acidification is removed by filtration or aqueous phase separation before the dehydration step.
When acylation chemistry requires phenylacetyl chloride, sodium phenylacetate is first acidified and dried; residual moisture is reduced below 0.05% before thionyl chloride is added. The chlorination is run in a glass-lined reactor with sulfur dioxide and hydrogen chloride off-gases sent to a caustic scrubber. Thionyl chloride is charged at 1.05–1.10 mol per mole of phenylacetic acid, and the reactor is maintained below 60 °C until gas evolution ceases. Vacuum distillation at 2–5 kPa then yields phenylacetyl chloride, which is a lachrymator and requires closed transfer. The acid chloride is used to acylate amines, alcohols, and thiols in pharmaceutical and agrochemical intermediate production. Direct treatment of the sodium salt with thionyl chloride is avoided because the salt form does not give controlled conversion and increases by-product formation; acidification and drying are therefore mandatory upstream steps.
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Sodium phenylacetate (CAS 114-70-5; C8H7NaO2; molecular weight 158.13 g/mol) is the sodium salt of phenylacetic acid, supplied as a white to off-white crystalline powder that is freely soluble in water. The product is not differentiated by consumer-style model numbers; commercial material is specified by grade, monograph, and certificate-of-analysis data. Pharmaceutical-grade sodium phenylacetate is used as an active pharmaceutical ingredient in the FDA-approved injectable product Ammonul, where it is co-formulated with sodium benzoate at 100 mg/mL of each component. Technical-grade material is handled as a fermentation precursor in penicillin G production, and research-grade material is used for experimental nitrogen-scavenging studies. The free acid has a reported pKa near 4.31; salt formation yields a water-soluble powder suitable for parenteral formulation and aqueous bioprocess feeding.
Compendial control for sodium phenylacetate as a parenteral drug substance includes identification, assay, water content, residue on ignition, residual solvents, elemental impurities, and bacterial endotoxins. The table below summarizes the specification framework commonly encountered; a specific manufacturer’s certificate of analysis and the current USP-NF monograph text govern any summarized range. Solid-state characterization for parenteral drug substance includes X-ray powder diffraction to confirm crystalline form, and residual solvent analysis by headspace gas chromatography. Because sodium phenylacetate is hygroscopic, moisture ingress during dispensing can shift water content and flow properties; production suites therefore maintain controlled relative humidity below the limit specified in the site master file. Reference retention samples are stored in tight containers to support lot-to-lot comparability.
| Parameter | Test or reference | Typical acceptance basis | Operational note |
|---|---|---|---|
| Appearance | Visual | White to off-white crystalline powder | Free of visible extraneous matter |
| Identification | IR or HPLC | Matches reference standard | USP <197> |
| Assay | HPLC/UV | 98.0–102.0% on dried basis | Compendial range; verify against current monograph |
| Water content | Karl Fischer | ≤1.0% for anhydrous grade | USP <921> |
| Residual solvents | Headspace GC | Class 3 limits unless justified | USP <467> |
| Elemental impurities | ICP–MS | ICH Q3D limits | USP <232> and <233> |
| Bacterial endotoxins | LAL | Derived from maximum dose | USP <85>; parenteral grade only |
| Sodium content | Calculated from formula | 14.5% by mass | Used in parenteral sodium-load calculations |
Fermentation-grade material is not interchangeable with the parenteral drug substance; endotoxin and elemental impurity controls may be reduced or omitted, and the residual solvent profile is tailored to fermentation feed rather than injectable use. The compendial and technical grades share the same molecular identity but diverge at release testing and documentation.
The therapeutic action of sodium phenylacetate does not rely on direct chemical binding of free ammonia in plasma. In the liver and kidney, phenylacetate is activated to phenylacetyl-CoA and conjugated with glutamine to yield phenylacetylglutamine, which is then excreted by the kidney. One mole of phenylacetate removes 2 mol of nitrogen because each phenylacetylglutamine molecule carries two nitrogen atoms. This stoichiometry is higher than that of sodium benzoate, which conjugates glycine to form hippurate and removes 1 mol of nitrogen per mole of benzoate. The system depends on adequate glutamine synthesis from ammonia and on intact renal excretion of the conjugate; elimination can be reduced in renal impairment and in states with impaired liver perfusion or metabolic decompensation.
The conjugation reaction is enzyme-dependent and saturable. In acute hyperammonemia, phenylacetate and benzoate co-administration increases nitrogen excretion through two separate amino acid pools; this reduces the risk of saturating a single pathway. However, the rate of ammonia reduction is not instantaneous because glutamine must first be synthesized and then conjugated; plasma ammonia may continue to rise during the early infusion interval, requiring extracorporeal removal if the clinical response is inadequate.
Administration of the intravenous co-formulation in acute hyperammonemia begins with a loading dose followed by maintenance infusion. For patients weighing more than 20 kg, the loading dose is 5.5 g/m² of sodium phenylacetate and 5.5 g/m² of sodium benzoate, diluted in 10% dextrose injection and infused over 90–120 minutes; the maintenance dose is the same amount given over 24 hours. For patients weighing 20 kg or less, the dose is 250 mg/kg of each component. The undiluted injection is hypertonic and must be diluted before use; central venous administration is standard because of venous irritation and extravasation risk. Plasma ammonia, serum electrolytes, and neurological status are monitored at intervals determined by clinical protocol. Compatibility data with other infusion solutions and additional drugs are limited, so the labeled admixture is prepared in 10% dextrose injection and is not mixed with unauthorized additives. The maintenance infusion should be prepared in the same diluent and administered at a controlled rate using an infusion pump; the hypertonic admixture is not suitable for rapid peripheral bolus injection.
Selection among nitrogen-scavenging agents depends on route, sodium load, and chronicity. Sodium phenylacetate is an intravenous active moiety; sodium benzoate is frequently combined with it; sodium phenylbutyrate and glycerol phenylbutyrate are oral prodrugs used in long-term management. The table compares key operational variables.
| Agent | Route and presentation | Metabolic pathway | Nitrogen removed | Sodium load | Operational constraint |
|---|---|---|---|---|---|
| Sodium phenylacetate | IV injection | Conjugation with glutamine to phenylacetylglutamine | 2 mol N per mol | 1 mol Na per mol; 14.5% w/w | Hypertonic; requires dilution and central venous access |
| Sodium benzoate | IV injection | Conjugation with glycine to hippurate | 1 mol N per mol | 1 mol Na per mol; 16.0% w/w | Used together with phenylacetate for additive clearance |
| Sodium phenylbutyrate | Oral tablet/powder | β-oxidation to phenylacetate, then conjugation with glutamine | 2 mol N per mol after conversion | 1 mol Na per mol | Chronic oral dosing; tablet burden and sodium intake |
| Glycerol phenylbutyrate | Oral liquid | Hydrolysis to release three phenylbutyrate units, then β-oxidation | Up to 6 mol N per mol parent after full conversion | Sodium-free | No salt load, but requires digestion and higher molar dose due to molecular weight |
The intravenous co-formulation is used for acute hyperammonemic episodes because it provides two independent conjugation routes; oral prodrugs are ordinarily reserved for maintenance therapy once enteral access is stable and sodium intake must be managed. Oral sodium phenylbutyrate has a molecular weight of 186.18 g/mol and a sodium content of approximately 12.4% by mass. Glycerol phenylbutyrate is sodium-free but must be hydrolyzed by digestive enzymes before the phenylbutyrate units are available for β-oxidation. The intravenous phenylacetate formulation bypasses enteral absorption and first-pass metabolism, which is clinically relevant during acute decompensation when gut function is unreliable. The co-formulation with sodium benzoate adds a second conjugation pathway; one mole of each intravenous component removes approximately 3 mol of nitrogen in total.
In penicillin G fermentation, sodium phenylacetate supplies the phenylacetyl side-chain precursor for benzylpenicillin biosynthesis by Penicillium chrysogenum. The sodium salt is preferred over free phenylacetic acid where aqueous feeding, pH control, and precursor solubility are limiting. Production-scale penicillin fermentations use stainless steel fed-batch bioreactors with separate sterile feed lines for pH correction and precursor delivery. The sodium phenylacetate feed is not added as a single bolus; it is metered to avoid transient pH depression and to maintain the dissolved oxygen and carbon dioxide profiles recorded by off-gas analyzers. Feeding strategies balance precursor supply against growth inhibition; specific fed-batch profiles are strain- and process-specific, and published data for a particular production line are limited. Technical-grade material used in fermentation is released against manufacturer-specific specifications that typically omit parenteral endotoxin controls but retain phenylacetate content and residual solvent limits. No single industrial model defines the product; differentiation occurs through purity profile, particle size, and batch-to-batch consistency.
The principal operational limitations for sodium phenylacetate are sodium load, hypertonicity, and dependence on renal clearance. At a dose of 5.5 g/m² of sodium phenylacetate, the sodium contribution is approximately 0.80 g/m²; the co-administered sodium benzoate at 5.5 g/m² adds approximately 0.88 g/m². The combined sodium load of about 1.68 g/m² must be included in fluid and electrolyte calculations for patients with cardiac failure, renal impairment, or hypernatremia. For a typical adult body surface area of 1.73 m², the combined sodium load from the loading dose is approximately 2.9 g. This does not include sodium from diluent, which is present in 10% dextrose injection only in negligible amounts unless sodium bicarbonate or other sodium salts are co-administered. Patients with pre-existing hypernatremia, edema, or reduced left ventricular function require a cumulative sodium budget before infusion begins.
Renal excretion of phenylacetylglutamine is the elimination route; renal impairment may reduce clearance and allow accumulation of the conjugate and parent compound. Monitoring of serum sodium, potassium, bicarbonate, and plasma ammonia is performed during and after infusion. Sodium phenylacetate drug substance should be stored in tightly closed containers protected from moisture; aqueous admixtures are used within the stability window validated by the compounding facility. Compatibility with other agents is not extensively characterized, so the infusion is not mixed with unauthorized additives, and central line lumens should be dedicated to the scavenger infusion unless compatibility is documented. Fermentation-grade material is not interchangeable with compendial drug substance because endotoxin, elemental impurity, and residual solvent controls differ.
