| HS Code | 934590 |
| Product Name | Pharmaceutical Grade Sodium Hyaluronate (Hyaluronic Acid) Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Synonyms | Sodium Hyaluronate, Hyaluronic Acid Sodium Salt, Sodium Hyaluronan, HA Sodium Salt |
| Cas Number | 9067-32-7 |
| Molecular Formula | (C14H20NNaO11)n |
| Molecular Weight | Variable, typically 0.5-3.0 MDa depending on grade |
| Grade | Pharmaceutical Grade / API Grade |
| Source | Microbial fermentation or rooster comb |
| Appearance | White to off-white powder or granules |
| Assay | 95.0%-105.0% (dry basis) |
| Ph | 5.0-8.5 (1% aqueous solution) |
| Solubility | Freely soluble in water; practically insoluble in organic solvents |
| Heavy Metals | ≤10 ppm |
| Bacterial Endotoxins | ≤0.05 EU/mg for injectable grade |
| Microbial Limits | TAMC ≤100 CFU/g; TYMC ≤10 CFU/g; absence of specified pathogens |
| Moisture Content | ≤10.0% |
| Protein Content | ≤0.1% |
| Nucleic Acid Content | ≤0.1% |
| Sodium Content | 2.5%-4.0% |
| Viscosity | Variable depending on molecular weight and concentration |
| Specific Rotation | -70° to -80° |
| Loss On Drying | ≤10.0% |
| Sterility | Sterile for injectable grade; non-sterile for oral solid dosage grade |
| Dosage Forms | Tablet, capsule, granule, injection |
| Route Of Administration | Oral and injectable |
| Storage Conditions | Store in a cool, dry place, protected from light, in tightly sealed containers |
| Shelf Life | 24-36 months when stored properly |
| Packaging | 1 kg/bag, 5 kg/drum, 10 kg/drum, or as requested |
| Regulatory Compliance | USP, EP, ChP, or customer-specific specifications |
As an accredited Pharmaceutical Grade Sodium Hyaluronate (Hyaluronic Acid) 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.
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Pharmaceutical-grade sodium hyaluronate with bulk density below 0.20 g/cm³ and tapped density above 0.40 g/cm³ under USP <616> Method I creates a wide void-size distribution in a rotary press feed frame. On a 10-station rotary press with B tooling, direct compression above 3.0% w/w API becomes process-sensitive because electrostatic surface charge increases die-wall adhesion and causes die fill weight variation greater than 2.5% at turret speeds above 30 rpm. Pre-sieving the sodium hyaluronate through a 425 μm sieve and pre-blending with microcrystalline cellulose at a 1:4 ratio for 20 min in an 800 L V-blender rotating at 12 rpm reduces blend RSD to below 5.0%. The final blend is compressed at 6–12 kN main force with 2–4 kN pre-compression; higher main force increases tablet hardness above 60 N but triggers capping because the polymer recovers elastically after decompression. Content uniformity is acceptable when the acceptance value under USP <905> is ≤15; if the API is not pre-blended, superpotent tablets are detected at the beginning and end of the batch. Loss on drying of the final blend is held at 2.0–4.0% by USP <731>; below 2.0% the powder charges electrostatically, and above 4.0% the tablets show prolonged disintegration.
For dry granulation, roller compaction at 4–8 MPa roll pressure and milling through a 1.0 mm screen produces granules with bulk density 0.35–0.55 g/cm³ and flow index 8–12 mm under USP <1174>. Ribbons must be milled within 30 min of compaction; otherwise moisture uptake at relative humidity above 60% RH causes screen blinding on the oscillating granulator. Lubrication with 0.5% w/w magnesium stearate is limited to 3 min because longer blending coats the granules and reduces tablet tensile strength by more than 15%. Disintegration in 0.1 N HCl at 37 °C according to USP <701> is typically 8–15 min, but if granule moisture falls below 2.0%, disintegration time may exceed 20 min because the compacted granules become hydrophobic and resist liquid penetration.
On an intermittent-motion capsule filler with dosator nozzles, the compressibility of sodium hyaluronate plugs changes with surface moisture more than with total water content. At 25 °C and 30% RH, a 20 mg dose in a size 3 capsule can be filled with plug weight RSD below 3.5% when dosing tubes of 25 mm length are used with a compression spring preload of 5 N. If ambient relative humidity rises above 40%, the powder surface adsorbs water rapidly, capillary bridges increase internal friction, and plug weight drifts by more than 6% within 30 min. The effect is more severe with dosator fillers than with tamping-pin machines because the dosator chamber shears the powder plug during ejection. Tamping-pin fillers set to 3–5 mm pin depth and 1–3 tamping stations produce plug hardness of 4–8 N; above 8 N, plug ejection becomes irregular and capsule body deformation occurs. Finished capsules are tested by USP <905> content uniformity and USP <701> disintegration; the capsule shell can delay disintegration by 2–4 min compared with the unencapsulated powder. The process boundary is therefore relative humidity ≤40% and powder loss on drying 2.0–4.0% by USP <731>; above these limits, static charges and agglomeration cause batch failure before compression or filling yield drops below 90%.
Top-spray granulation of a 70:30 blend of sodium hyaluronate and microcrystalline cellulose in a fluid-bed granulator is run with an aqueous binder containing 3% w/w hypromellose E5. Binder spray rate is set at 8–15 g/min for a 5 kg charge, product temperature at 28–34 °C, and atomization air pressure at 1.5–2.0 bar. The endpoint is reached when the product temperature rises 2 °C above the wet-bulb line and the exhaust air flow falls by 10–15% of the initial value; reaching this point later than 25 min usually indicates binder over-spray and produces agglomerates larger than 2 mm. The granulate is dried at 40–45 °C until loss on drying returns to 2.0–4.0% by USP <731>. If residual moisture is below 2.0%, tablet tensile strength at 12–16 kN main compression force is reduced because the granule structure loses plasticizing water; above 4.0%, the material blocks the 1.0 mm screen during dry milling. Disintegrant is added extragranular after drying because intragranular addition of croscarmellose sodium in a wet granulation step swells prematurely and produces tablets with disintegration above 20 min in USP <701> testing. Tablets produced from this granulation at 12–16 kN compression force show hardness 40–80 N and friability below 1.0% by USP <1216>. The critical control window is the spray rate/product temperature relationship; a deviation of ±2 °C in product temperature is sufficient to shift the granule size distribution from 100–500 μm to a bimodal distribution containing 10–20% oversized agglomerates above 850 μm.
| Parameter | Direct compression | Dry granulation | Wet granulation |
|---|---|---|---|
| Moisture endpoint by USP <731> | 2.0–4.0% | 2.0–4.0% | 2.0–4.0% |
| Bulk density by USP <616> | 0.20–0.35 g/cm³ | 0.35–0.55 g/cm³ | 0.45–0.65 g/cm³ |
| Main compression force | 6–12 kN | 8–16 kN | 12–16 kN |
| Disintegration time by USP <701> | 5–15 min | 8–15 min | 10–20 min |
| Primary failure mode | Capping and static adhesion | Screen blinding and moisture uptake | Overwetting and bimodal agglomeration |
Terminal steam sterilization at 121 °C for 15 min is generally avoided for high-molecular-weight sodium hyaluronate because hydrolytic chain scission reduces intrinsic viscosity by more than 30% and broadens the molecular-weight distribution toward oligosaccharides. For a 0.5% w/v solution with molecular weight below 1.0 MDa, sterile filtration through a 0.22 μm polyethersulfone membrane is feasible when the feed temperature is maintained at 35–40 °C; above 1.5 MDa, filter throughput drops below 1 L/10 cm² at 0.5 MPa differential pressure. A staged filtration train consisting of a 1.2 μm polypropylene prefilter, a 0.45 μm polyethersulfone membrane, and a final 0.22 μm sterilizing-grade membrane is used to prevent premature fouling. After filtration, the solution is held no longer than 8 h at 20 °C before aseptic filling under ISO 13408-1; longer hold times produce a viscosity loss of 2–5% per 24 h. For finished injectable product, endotoxin content is controlled to less than 0.5 EU/mg by USP <85>, sterility is confirmed by USP <71>, and particulate matter is controlled to ≤6000 particles/container at ≥10 μm and ≤600 particles/container at ≥25 μm under USP <788>. Formulation pH is held at 6.5–7.5 with a phosphate buffer; below 6.0, acid-catalyzed hydrolysis accelerates and above 8.0, the polymer is susceptible to oxidation and chain cleavage. The osmolality of a 1.0% w/v solution is adjusted to 270–330 mOsm/kg with sodium chloride or mannitol before filtration.
Ophthalmic formulations containing 0.1–0.3% w/v sodium hyaluronate are compounded in a sterile buffer system at pH 7.0–7.4 and osmolality 280–320 mOsm/kg, using water for injection as the vehicle. The high-viscosity fraction is hydrated for 4–8 h under low-shear mixing at 50–100 rpm; high-shear dispersion above 500 rpm reduces the zero-shear viscosity by more than 10% through mechanical chain scission. Solutions are filtered through a 0.22 μm capsule filter at 25–35 °C; cold filtration at 5 °C is not used because viscosity rises and filter flux falls below 0.5 L/h/10 cm². The final solution is filled into blow-fill-seal units or glass ophthalmic containers and tested for sterility by USP <71>, endotoxin by USP <85>, and particulate matter by USP <789>. Viscosity measured with a cone-and-plate rheometer at 1 s⁻¹ and 25 °C is held within ±10% of the target value; drops below this range indicate polymer degradation or improper hydration. Benzalkonium chloride at 0.004–0.01% w/v may be used in multi-dose ophthalmic products, but the anionic polymer can reduce preservative availability; single-dose units are therefore manufactured without preservatives. Storage is maintained at 15–25 °C; storage above 30 °C for more than 3 months results in measurable viscosity loss and may shift product pH below 6.5 due to buffer equilibrium changes.
Lyophilization of sodium hyaluronate for intra-articular injection is performed from a 1.0% w/v solution with 2.0% w/v mannitol as a bulking agent, filled at 1.0 mL nominal volume into 2 mL type I glass vials. The freeze-thaw behavior is characterized by a rapid increase in viscosity during the cooling ramp; the shelf temperature must be reduced to −45 °C over 2 h to avoid cryoconcentration gradients that produce a dense skin on the residual liquid surface. Primary drying is conducted at −20 °C and 0.15 mbar for 48 h; if the product temperature exceeds −35 °C, the cake collapses because the amorphous phase softens before ice sublimation is complete. Secondary drying at 25 °C for 6 h yields residual moisture below 1.0% by USP <731>. Reconstitution with water for injection should yield a clear solution within 60 s; longer reconstitution indicates incomplete lyophilization or collapse. The lyophilized cake is tested for endotoxin by USP <85>, sterility by USP <71>, and particulate matter by USP <788>. The moisture limit is critical because residual moisture above 1.5% accelerates degradation during storage and reduces molecular weight by more than 10% over 6 months at 25 °C.
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Pharmaceutical grade sodium hyaluronate, the sodium salt of hyaluronic acid, is a fermentation-derived linear glycosaminoglycan composed of repeating β-(1→4)-D-glucuronic acid and β-(1→3)-N-acetyl-D-glucosamine disaccharide units. The product is supplied as model SH-PG-L, SH-PG-M, and SH-PG-H, covering nominal weight-average molecular weights of 0.1–0.3 MDa, 0.8–1.5 MDa, and 1.8–2.5 MDa as determined by size-exclusion chromatography with multi-angle laser light scattering. These API grades are released for use in tablets, capsules, granules, oral solutions, and injectable formulations; injectable use requires compliance with sterility, bacterial endotoxin, and particulate matter controls. Compared with cosmetic-grade material or uncertified hyaluronic acid, the product line is tested against United States Pharmacopeia and European Pharmacopoeia monographs for Sodium Hyaluronate, with additional release tests for residual proteins, elemental impurities, and microbial limits. The sodium salt form is preferred over the protonated hyaluronic acid because of its aqueous solubility and near-neutral pH in solution; the free acid is less soluble and can form acidic solutions when reconstituted at high concentration.
The release specification is defined by orthogonal methods rather than viscosity alone. Intrinsic viscosity per Ph. Eur. 2.2.9 correlates with molecular weight but does not replace SEC-MALS for weight-average molecular weight and dispersity. Protein content is determined by Lowry assay; bacterial endotoxins are determined by limulus amebocyte lysate testing under USP <85>. Residual moisture is controlled because high-molecular-weight sodium hyaluronate gains mass rapidly above 60% relative humidity, and moisture absorbed during dispensing can alter dry blend flow and tablet hardness. The following representative release limits apply to fermentation-derived pharmaceutical grade material; exact compendial limits may vary by monograph edition.
| Parameter | Test method | Typical release limit |
|---|---|---|
| Appearance | Visual inspection | White to off-white powder or granules |
| Intrinsic viscosity | Ph. Eur. 2.2.9 | 0.5–3.0 dL/g depending on model |
| Weight-average molecular weight | SEC-MALS | 0.1–2.5 MDa depending on model |
| Loss on drying | USP <731> | ≤10.0% |
| Protein content | Lowry assay | ≤0.1% w/w |
| Bacterial endotoxins | USP <85> | ≤0.5 EU/mg injectable; ≤0.05 EU/mg ophthalmic/viscoelastic |
| Microbial enumeration | USP <61>, <62> | Total aerobic microbial count ≤100 CFU/g; combined yeast and mould ≤10 CFU/g |
Intrinsic viscosity release limits are grade-specific because the relationship between molecular weight and intrinsic viscosity follows Mark–Houwink parameters that vary with solvent and ionic strength. For sodium hyaluronate in 0.15 M sodium chloride at 25°C, the exponent is commonly around 0.67–0.72; small changes in molecular weight therefore produce measurable but not linear changes in intrinsic viscosity. Manufacturers using capillary viscometry per Ph. Eur. 2.2.9 should cross-validate the result against SEC-MALS for release of injectable grade, because viscometry alone may not detect a broadened molecular weight distribution or low-molecular-weight tailing.
Viscosity of sodium hyaluronate solutions is strongly dependent on molecular weight, concentration, and shear rate. At 1.0% w/v and 25°C, the 0.3 MDa grade may show an apparent viscosity near 10 mPa·s, whereas the 2.5 MDa grade can exceed 1,000 mPa·s at low shear. This non-linear relationship controls injectable formulation limits: for subcutaneous or intra-articular administration, high-molecular-weight material is usually formulated at 0.8–2.0% w/v, but the resulting dynamic viscosity can exceed 100,000 mPa·s at low shear, requiring positive-displacement filling equipment and wide-bore needles. Published syringeability data for 2.5 MDa solutions through 27G needles at 25°C indicate high extrusion force; warming to 30–35°C and using 25G needles reduces force but may not be acceptable for all injection routes.
Microbial fermentation using Streptococcus zooepidemicus or Bacillus subtilis under controlled carbon and nitrogen feed yields high-molecular-weight sodium hyaluronate with lower protein and nucleic acid residues than rooster comb extraction. Animal-derived material carries inherent risk of avian protein, nucleic acid, and possible adventitious agents; injectable applications therefore require more extensive viral validation. The fermentation route is compatible with ICH Q5A viral safety principles when downstream processing is appropriately validated, but endotoxin control is critical because gram-negative fermentation organisms contribute lipopolysaccharide. Purification by diafiltration, activated carbon treatment, and ethanol precipitation reduces protein to ≤0.1% w/w and endotoxin to injectable limits, yet over-processing can reduce molecular weight below the declared grade. The sodium hyaluronate API is also differentiated from cosmetic grade by absence of uncontrolled low-molecular-weight fragments and by batch-to-batch molecular weight consistency; cosmetic grade is not routinely tested for bacterial endotoxins or injectable particulate matter, and its molecular weight distribution is often wider. Cross-linked sodium hyaluronate used in dermal fillers and viscosupplementation is a chemically modified hydrogel and is not interchangeable with linear API; it is regulated as a medical device and carries residual crosslinker limits rather than API monograph limits.
Direct compression of sodium hyaluronate is limited by low bulk density of approximately 0.1–0.3 g/mL, electrostatic charging, and poor flow. Blending with microcrystalline cellulose in a V-blender at 25 rpm for 15–20 min improves uniformity, but the addition of colloidal silicon dioxide above 1.0–2.0% may enhance flow without excessive dusting. Die fill on high-speed rotary tablet presses is typically restricted to speeds below 40 rpm unless the formulation is granulated. Upon contact with dissolution medium, sodium hyaluronate forms a viscous gel layer that can retard release; this property is exploited in sustained-release matrices but requires dissolution testing in USP apparatus II with controlled agitation, because gel adherence can interfere with sink conditions. Capsule formulations containing 50–200 mg sodium hyaluronate per unit are manufactured under controlled relative humidity not exceeding 40%; higher humidity causes powder agglomeration and sticking to capsule filling machine contact parts.
Wet granulation with water as the granulating fluid is often unsuccessful because surface hydration generates a mucilaginous mass that fouls high-shear granulator blades. Hydroalcoholic granulation vehicles such as ethanol/water mixtures from 70:30 to 90:10 v/v reduce gel layer formation but require explosion-proof granulation suites and additional solvent recovery. Roller compaction with a roll force of 5–15 kN/cm and screen milling to 0.8–1.5 mm granules produces free-flowing material without exposing the polymer to thermal drying. Compact hardness must be monitored because excessive roll force can induce polymer chain orientation or glass transition that slows dissolution; published data for this specific configuration is limited, so scale-up trials typically evaluate dissolution at pilot scale before committing to commercial batch sizes.
In high-shear granulation, the rate of water addition and impeller tip speed control the onset of viscous gel formation. At impeller tip speeds above 4 m/s, the shear energy can generate heat that promotes partial hydration of sodium hyaluronate particles even before uniform liquid distribution is achieved. The resulting agglomerates are prone to sticking on the granulator bowl, and end-point detection by power consumption becomes unreliable. A more reproducible approach is to pre-blend sodium hyaluronate with a hydrophobic or rapidly wetting diluent, or to use a non-aqueous binder solution, before low-shear granulation. This processing boundary should be considered during formulation development for granules intended for oral sachets or dispersible tablets.
| Model | Nominal weight-average molecular weight | Typical intrinsic viscosity | Primary pharmaceutical use |
|---|---|---|---|
| SH-PG-L | 0.1–0.3 MDa | 0.5–1.0 dL/g | Sterile-filterable solutions, oral solutions |
| SH-PG-M | 0.8–1.5 MDa | 1.5–2.5 dL/g | Tablets, capsules, intra-articular injections |
| SH-PG-H | 1.8–2.5 MDa | 2.5–3.5 dL/g | Controlled-release matrices, viscosupplementation |
Weight-average molecular weight and intrinsic viscosity are critical for injectable grade because they affect filtration and sterility assurance. For low-molecular-weight sodium hyaluronate of 0.1–0.3 MDa, 0.2 µm membrane filtration may be possible at concentrations up to 2.0% w/v, but medium and high grades often require 0.45 µm prefiltration and/or dilution. Terminal sterilisation by steam at 121°C for 15 min typically reduces molecular weight; the extent of chain scission is pH-dependent, and phosphate-buffered solutions at pH 7.4 exhibit less viscosity loss than unbuffered acidic solutions. Aseptic filtration and filling are therefore preferred for high-molecular-weight injectable products where preservation of viscoelastic properties is required. The operational boundary is dictated by the combination of molecular weight, concentration, and filter membrane area: high-molecular-weight sodium hyaluronate at 2.0% w/v may require transmembrane pressure below 1.0 bar and pre-warmed solution to maintain filter flux.
Storage of sealed containers at 2–8°C is recommended for high-molecular-weight injectable grade; storage above 25°C and relative humidity above 60% accelerates moisture uptake, oxidative chain scission, and microbial growth risk. The powder should not be blended with strong oxidising agents or cationic polymers because electrostatic complexation can produce insoluble aggregates. For oral solid dosage forms, pre-drying at 40–50°C for 2–4 h is required when moisture content exceeds 8.0% w/w before direct compression. These boundary conditions are derived from compendial stability requirements and common pharmaceutical manufacturing practice; they define the practical operating window for the API across tablet, capsule, granule, oral solution, and injectable applications.
