4-Hydroxyphenylacetic acid, CAS 156-38-7, is supplied as a pharma-grade active pharmaceutical ingredient for tablet, capsule, granule, oral solution, and injectable dosage forms. The molecular formula is C₈H₈O₃, and the molecular weight is 152.15 g/mol. The product is a white to off-white crystalline powder with a reported melting range of 149–151 °C. No single model number is defined in public pharmacopoeial monographs; the grade is identified by the manufacturer’s product code, batch certificate, and route-specific release specification such as “oral grade” or “parenteral grade.” For oral solid dosage forms, particle size, bulk density, and moisture are controlled to support blend flow and content uniformity. For parenteral use, the same chemical entity is released with tightened limits for bacterial endotoxin, bioburden, and subvisible particulate matter. Because the molecule carries a para-hydroxyl substituent and a carboxylic acid group, its hydrogen-bonding capacity, melting point, moisture affinity, and solid-state behavior differ from those of phenylacetic acid and the meta-hydroxy positional isomer.

What Limits the Injectable Grade for Parenteral Administration?

For parenteral use, release controls must address pyrogenicity and particulate cleanliness before the material can be dissolved or lyophilized. Bacterial endotoxin limits follow USP <85> and are derived from the maximum intended dose; a parenteral grade may be released with an endotoxin limit of ≤ 0.25 EU/mg when the maximum dose is low or ≤ 0.10 EU/mg when the intended dose is high, but the limit remains dose-justified and product-specific. The bulk API is not sterile by default. Sterility of the finished injection is achieved by aseptic filtration through a 0.22 µm sterilizing-grade membrane and is verified according to USP <71>. Subvisible particulate matter in the finished injection is controlled by USP <788>; for large-volume parenterals the light obscuration method permits no more than 25 particles/mL ≥ 10 µm and no more than 3 particles/mL ≥ 25 µm. Injectable-grade powder should be sieved through a 60-mesh or 80-mesh screen before dissolution or filling. Moisture content is controlled by USP <921> Method I or Karl Fischer coulometry, with a typical loss-on-drying criterion of ≤ 0.5% for lyophilization feedstock. The acidic carboxylic acid group can depress solution pH; therefore, buffering with sodium hydroxide or tromethamine is required to maintain a target pH of 6.0–7.4 before sterile filtration. Terminal sterilization is possible only after compatibility with heat and pH is demonstrated; published data for this specific molecule under all autoclave and radiation modes is limited, leaving aseptic filtration as the conservative default for injectable-grade processing.

When lyophilization is used for injectable presentation, the API is dissolved in a buffered vehicle at pH 6.0–7.0, filtered, filled into 10 mL or 20 mL glass vials, and freeze-dried. The lyophilization cycle must prevent cake collapse, melt-back, and residual moisture uptake. A representative cycle may include freezing at −45 °C, primary drying at −20 °C with chamber pressure of 50–150 mTorr, and secondary drying at 25 °C for 6–12 h, but the actual recipe is product and vial specific. The reconstituted solution is tested for clarity, color, pH, and subvisible particulate matter according to USP <788> and USP <630>. Because the para-phenolic hydroxyl group can undergo autoxidation in neutral to alkaline aqueous media, nitrogen sparging and light protection are applied during compounding and storage. Stability programs follow ICH Q1A(R2) with storage at 25 °C/60% RH and 40 °C/75% RH; primary stability batches are monitored for related substances, pH, and reconstitution time.

When the Carboxylic Acid Substituent Governs Solid-State Flow and Moisture Handling

In tablet and capsule manufacturing, the para-hydroxyl and carboxylic acid groups influence the powder’s response to mechanical stress, humidity, and lubricants. Direct compression is generally feasible when the particle size distribution is controlled; laser diffraction analysis according to ISO 13320:2020 may show a D90 below 250 µm for flowable direct compression grades, while low-dose blends may require a D50 below 75 µm to achieve content uniformity. Bulk and tapped density are measured according to USP <616>; compressibility index values above 25 indicate poor flow and require glidants such as colloidal silicon dioxide. The powder is blended in a V-blender or bin blender; contact surfaces may be 316L stainless steel or high-density polyethylene. Over-lubrication with magnesium stearate can reduce tablet tensile strength, because the carboxylic acid group may interact with the metal salt and form hydrophobic films on particle surfaces. Blending times longer than 5–10 min after lubricant addition should be avoided unless hardness and disintegration data support a longer interval.

For wet granulation, the binder may be hydroxypropyl cellulose or povidone in water; the use of water is limited by the API’s moderate aqueous solubility and potential for crystal habit changes during drying. A fluid-bed dryer with inlet air temperature not exceeding 60 °C is typical for tray or fluid-bed drying; endpoint is determined by loss on drying according to USP <731> and not by drying time alone. Roller compaction may be used when the API has low bulk density or poor flow. In a roller compactor, roll pressure is adjusted to produce granules with acceptable hardness and minimal fines; recompression on the tablet press is then used to form tablets with a target hardness of 5–12 kp depending on tablet size and shape, with friability not exceeding 1.0% after 100 drops according to USP <2040>. Disintegration time for immediate-release tablets is tested by USP <701>; formulations containing the API should disintegrate within 15–30 min in water at 37 °C, but the acceptance limit is product-specific.

The API is incorporated into oral solid dosage forms by direct compression, dry granulation, or wet granulation. For immediate-release tablets, a representative formulation may contain microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. The API is first geometrically diluted with the filler in a low-shear blender to avoid high-shear agglomeration. For high-dose tablets, the drug load may exceed 30% by weight; this requires attention to tensile strength because the API is a crystalline organic acid and may exhibit poor compactibility. Roller compaction is used to improve flow and bulk density; granules are milled through a 1.0 mm screen and recompressed on a rotary tablet press. Capsule filling on a dosator machine or a tamping pin machine requires consistent powder bed density; fill weight control is monitored by checkweigher feedback, and the blend must meet content uniformity according to USP <905>. Tablet hardness, friability, and disintegration are monitored according to USP <1217>, USP <2040>, and USP <701>. For prolonged-release tablets, matrix polymers such as hypromellose or polyethylene oxide may be used, but the release rate depends on the API’s pH-dependent solubility and must be tested in media at pH 1.2, 4.5, and 6.8 according to USP <711> and ICH Q2(R1).

Residual Solvent and Elemental Impurity Control Matrix

Release specifications include organic volatile impurities according to ICH Q3C, elemental impurities according to ICH Q3D, and microbial limits for nonsterile oral forms according to USP <1111>. Residual benzene, a class 1 solvent, is limited to 2 ppm; dichloromethane, a class 2 solvent, is limited to 600 ppm; methanol is limited to 3000 ppm. Residual solvents are determined by headspace gas chromatography according to USP <467>. Elemental impurities are screened by ICP-MS after closed-vessel acid digestion according to USP <233>; limits are set from the permitted daily exposure values in ICH Q3D and differ between oral and parenteral routes. Related substances are controlled by HPLC with UV detection at 220–254 nm; typical acceptance criteria for pharma-grade material are 98.0–102.0% assay on an anhydrous basis, total impurities ≤ 1.0%, and unspecified impurities ≤ 0.10%. Residual phenol and residual 4-hydroxyphenylacetonitrile-type intermediates are also screened when the synthetic route may introduce them.

An example release specification framework is provided in the following table.

For oral solutions and suspensions, the API is dissolved or suspended in a buffered vehicle adjusted to pH 6.0–7.4. Solution formulations may use sodium hydroxide or tromethamine to generate the carboxylate salt in situ; this increases aqueous solubility but may also increase chemical degradation rate at alkaline pH. The para-phenolic hydroxyl group is oxidation-sensitive; nitrogen sparging, chelating agents, and protection from light are commonly employed. If a suspension is used, viscosity and sedimentation behavior are controlled with xanthan gum or microcrystalline cellulose and sodium carboxymethyl cellulose; content uniformity is confirmed by USP <905>. Oral liquid formulations are preserved when required; unpreserved oral liquids are limited to single-use or short-dated multi-dose containers according to regional compendial expectations.

Aqueous solubility of 4-hydroxyphenylacetic acid is pH-dependent because the carboxylic acid group ionizes above pH about 4.4. In acidic media, the free acid form predominates and solubility is limited; in neutral to alkaline media, the carboxylate anion increases solubility. For oral immediate-release formulations, dissolution testing in 0.1 M hydrochloric acid and phosphate buffer at pH 4.5 and 6.8 may reveal incomplete release at low pH unless the formulation includes a disintegrant and appropriate particle size. For injectable formulations, the API is usually dissolved in a buffered aqueous vehicle at pH 6.0–7.0; solubility under these conditions is sufficient for typical dose strengths, but the exact saturation solubility should be measured at the intended temperature and ionic strength. Published solubility data in biorelevant media is limited.

Comparative Solid-State Data for Positional Isomers and the Unsubstituted Derivative

Compared with phenylacetic acid, the para-hydroxyl substitution on the aromatic ring increases molecular weight, melting point, and hydrogen-bonding capacity. Phenylacetic acid has a melting range of 76–77 °C; the introduction of the para-hydroxyl group raises the melting range to 149–151 °C and reduces volatility during drying and milling. Compared with 3-hydroxyphenylacetic acid, the para isomer has the same molecular formula and molecular weight but different crystal packing and possibly different solubility and intrinsic dissolution rate. The para isomer’s phenolic hydroxyl is less sterically hindered than the meta isomer and can more readily form intermolecular hydrogen bonds; this can increase agglomeration during milling and reduce flowability. However, published intrinsic dissolution rate data for the two positional isomers is limited, and formulators should compare batch-specific powder properties rather than relying on structural analogy alone.

The pharma grade is differentiated from technical-grade 4-hydroxyphenylacetic acid by the absence of process-related impurities that are permissible in industrial chemical applications but not in pharmaceutical use. Technical-grade material may contain higher levels of residual solvents, elemental impurities, and related substances, and it is not released with bacterial endotoxin or bioburden data. Pharma-grade material is manufactured under good manufacturing practice with validated cleaning, changeover, and batch traceability. The route-specific release specification for oral and injectable grades determines whether the material can be used in parenteral products; injectable-grade material may be used for oral dosage forms, but oral-grade material is not suitable for parenteral use unless it is repurified and re-released under parenteral specifications.

The free acid form of 4-hydroxyphenylacetic acid differs from its sodium or potassium salts in solubility, hygroscopicity, and solid-state stability. The free acid is typically preferred for tablet and capsule manufacture because of its lower hygroscopicity and higher melting point. For injectable solutions, the free acid is often converted to the carboxylate salt in situ during buffer preparation; this allows pH adjustment without introducing an additional salt solid. The sodium salt may be isolated if a high-pH solid form is required, but published data for the isolated salt form’s stability and handling is limited, and the free acid remains the more common commercial presentation.

Analytical methods for assay, related substances, and dissolution are validated according to ICH Q2(R1). Specificity is confirmed by forced degradation under acid, base, peroxide, heat, and light; the para-phenolic hydroxyl group may generate dimers or quinone-like oxidation products under oxidative conditions. HPLC methods should resolve the API from 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetonitrile, and phenylacetic acid if these are potential impurities. The assay working standard is qualified against a reference standard; chromatographic peak purity is confirmed by photodiode array detection. Quantitative nuclear magnetic resonance may be used as an orthogonal assay technique for batch release, particularly when the API is used without a pharmacopoeial monograph. Limit of detection and limit of quantitation for unspecified impurities should be below 0.05% and 0.10%, respectively, to support the listed acceptance criteria.

Operational boundaries: The powder should not be exposed to strong alkali in aqueous formulation without pH control, because the carboxylate salt can accelerate autoxidation of the para-phenolic ring. Avoid combination with strong oxidizing agents, hypochlorite, or concentrated nitric acid unless the synthetic or cleaning process has been formally validated. High-humidity environments above 60% RH may increase moisture uptake and reduce flow; pre-drying at 40–50 °C may be required if the powder has been stored in non-barrier packaging. The product is not intended for direct ingestion without formulation and pharmaceutical development. For injectable use, terminal heat sterilization should not replace aseptic filtration until degradation studies confirm that the impurity profile remains within specifications.

In production-scale handling, the API is transferred in low-dust high-containment systems such as split butterfly valves or flexible isolators, because fine particles can be generated during sieving and milling. The oral grade may be packaged in double polyethylene bags inside a fiber drum; the parenteral grade is typically packed in sterile or low-endotoxin packaging and may be double-bagged with desiccant. Storage is maintained at controlled room temperature, and the container closure system should protect against moisture and light. Process analytical technology may be used to monitor blend homogeneity by near-infrared spectroscopy; the calibration model must be developed specifically for the API peak at the chosen wavelength range. Published data on continuous direct compression for this specific compound is limited; batch processing remains the most documented route for tablet and capsule manufacture.