| HS Code | 193598 |
| Product Name | (S)-(+)-3-Hydroxytetrahydrofuran Pharma Grade API |
| Cas Number | 86087-24-3 |
| Molecular Formula | C4H8O2 |
| Molecular Weight | 88.11 g/mol |
| Appearance | Clear, colorless to pale yellow liquid |
| Purity | ≥99.0% |
| Specific Optical Rotation | +18.0° to +22.0° (c=1, methanol) |
| Assay Method | GC/HPLC |
| Solubility | Soluble in water, ethanol, ether, and acetone |
| Boiling Point | 181°C |
| Density | 1.111 g/cm³ |
| Refractive Index | 1.450-1.455 |
| Storage Conditions | Store in airtight container in a cool, dry place away from light and moisture |
| Shelf Life | 24 months when stored properly |
| Grade | Pharma Grade |
| Intended Dosage Forms | Tablet, Capsule, Granule, Injection |
| Administration Route | Oral and Injectable |
As an accredited (S)-(+)-3-Hydroxytetrahydrofuran 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 1 kg net double polyethylene-lined aluminum bottles under nitrogen, with tamper-evident closure, suitable for oral and injectable use. |
| Container Loading (20′ FCL) | One 20′ FCL loaded with drummed pharma-grade API, (S)-(+)-3-Hydroxytetrahydrofuran, for tablet, capsule, granule, oral, and injectable formulations. |
| Shipping | Shipment description: (S)-(+)-3-Hydroxytetrahydrofuran, pharma-grade API; clear, water-miscible liquid for oral/injectable dosage forms. If SDS flash point is ≥60°C, it is not regulated as dangerous goods. Pack in clean, sealed HDPE or stainless-steel drums under nitrogen, protected from light and moisture. Keep at 15–30°C during transport and include COA/SDS. |
| Storage | Store in tightly sealed, original containers under dry, cool conditions at controlled room temperature (20–25°C). Protect from light, moisture, and oxygen. Keep away from ignition sources and incompatible materials. For oral and injectable dosage forms, maintain strict hygiene and avoid contamination. Ensure container integrity until use. |
| Shelf Life | Shelf life is 24 months when stored under recommended conditions in the original tightly sealed container, protected from light and moisture. |
Liquid-state (S)-(+)-3-hydroxytetrahydrofuran is not charged directly into a high-speed rotary tablet press as a neat free form; pre-adsorption onto a porous pharmaceutical carrier is the first unit operation. The adsorption step is controlled by the carrier’s oil adsorption capacity, with a liquid-to-carrier mass ratio of 1.0:1.5 to 1.0:2.5 for magnesium aluminometasilicate or porous calcium silicate. The adsorbed phase is then blended with microcrystalline cellulose, croscarmellose sodium at 2.0–5.0% w/w, and magnesium stearate at 0.5–1.5% w/w to give a final active equivalent of 4.0–12.0% w/w in the tablet core. Direct compression is performed on a rotary press with B-tooling at 8–18 kN main compression force and 2–5 kN pre-compression; tablet hardness is maintained at 60–90 N to avoid fragmentation of the porous carrier. Batch release testing follows USP <905> uniformity of dosage units, USP <711> dissolution, ICH Q3C residual solvents, ICH Q3D elemental impurities, and 21 CFR 211.110 in-process sampling. No public pharmacopoeial monograph fixes these values for this exact molecule; the stated range is a processing boundary calibrated to carrier adsorption capacity and tablet tensile strength. The terminal finished product for this application block is an immediate-release film-coated tablet for oral administration.
Roller compaction is applied when the adsorbed pre-blend exhibits a bulk density below 0.40 g/cm³ and cannot be filled directly into hard capsules without unacceptable weight variance. The pre-blend is prepared with active liquid equivalent at 6.0–15.0% w/w of the final capsule fill weight, microcrystalline cellulose at 40.0–60.0% w/w, crospovidone at 3.0–6.0% w/w, and sodium stearyl fumarate at 1.0–2.0% w/w. Ribbon formation uses a roller compactor with an inclined screw feeder at roll pressure 40–70 kN and roll gap 1.0–2.0 mm; ribbon density is held at 0.70–0.85 g/cm³ to balance granule hardness and downstream dissolution. The ribbon is milled through a 0.8–1.0 mm screen at rotor speed 40–80 rpm, then filled into size 1 or size 0 hard gelatin or hypromellose capsules. Capsule manufacturing suites are operated under ISO 14644-1:2015 class 8 conditions. Release testing includes USP <711> dissolution, USP <905> uniformity of dosage units, and ICH Q3C residual solvent limits. Published data for this specific compound in roller-compacted capsule configuration is limited; the loading window is derived from carrier capacity and ribbon tensile strength rather than from a public monograph. The terminal finished product form is an oral hard capsule containing the carrier-adsorbed chiral active phase.
Fluid-bed top-spray granulation of the adsorbed active phase is used when the required oral granule dose cannot be met by direct compression because the free liquid carrier reduces blend flow function coefficient below 2.0. The granulation charge contains active liquid equivalent at 3.0–10.0% w/w, povidone K30 at 2.0–4.0% w/w, crospovidone at 2.0–5.0% w/w, and citric acid monohydrate at 0.5–1.0% w/w to adjust local pH. Top-spray granulation is conducted with inlet air temperature 50–65°C, product temperature 28–32°C, atomization air pressure 1.5–2.5 bar, and final granule moisture 1.0–2.0% w/w. The dried granulate is passed through a 0.8–1.25 mm sieve and filled into single-dose sachets. In-process control includes sieve analysis per USP <786>, moisture by Karl Fischer titration, and dissolution per USP <711>; residual solvent requirements are controlled under ICH Q3C Table 3. The absence of a public monograph for this molecule means the active loading is limited by granule density and flow rather than a compendial fixed ratio. Sachet filling delivers a single-dose oral granule for direct administration or reconstitution.
Aseptic lyophilization of the (S)-(+)-3-hydroxytetrahydrofuran-derived injectable phase requires a formulation screen for collapse temperature and glass transition temperature before fill-finish. The pre-lyophilization solution contains active at 5.0–15.0 mg/mL, mannitol at 25.0–35.0 mg/mL, and a citrate or phosphate buffer at 10–20 mM, adjusted to pH 6.5–7.4. The solution is filtered through a 0.22 µm PVDF/PES membrane into sterile Type I glass vials, and vials are partially stoppered. Freezing is performed to -40°C with a hold time of 2 h. Primary drying shelf temperature is -20°C, chamber pressure is 80–120 mTorr, and ramp rate is 0.5°C/min. Secondary drying is conducted at 25°C for 5–10 h. Release and process control follow USP <1>, USP <788>, USP <85>, and EU GMP Annex 1 requirements for terminally sterilized or aseptically processed injectable products. Published data for this specific compound is limited; cycle parameters are format-specific and require confirmation by freeze-dry microscopy and thermal analysis. Fill-finish yields a lyophilized powder for injection in single-dose Type I glass vials.
Aseptic solution manufacture of the injectable form of (S)-(+)-3-hydroxytetrahydrofuran requires a solubility and pH stability screen before filtration. The solution formulation contains active at 1.0–8.0 mg/mL, sodium chloride at 0.7–0.9% w/w for isotonicity, citrate buffer at 10–20 mM, and pH adjusted to 6.8–7.4 with water for injection q.s. Bioburden reduction is performed through a 0.45 µm filter, followed by sterile filtration through a 0.22 µm PVDF or PES membrane. Terminal sterilization at 121°C for 15 min may be applied only when thermal stability data support a D121 value above 1.5 min; otherwise aseptic filtration is performed in Grade A unidirectional airflow with ISO 14644-1:2015 class 5 background. Quality release includes USP <1>, USP <788>, USP <785>, USP <85>, 21 CFR 211.167, and EU GMP Annex 1. Published data for this exact molecule as a ready-to-inject solution is limited; osmolality, particulate matter, and filter compatibility must be confirmed on each batch. The resulting terminal product is a single-dose injectable solution in Type I borosilicate glass vials.
This route is considered only when a solid-state salt or carrier-adsorbed phase with acceptable thermal stability is available for extended-release matrix formation. The matrix formulation contains active equivalent at 8.0–20.0% w/w, hypromellose K4M at 25.0–35.0% w/w, ethylcellulose at 10.0–20.0% w/w, microcrystalline cellulose at 20.0–30.0% w/w, glyceryl behenate at 2.0–5.0% w/w, and magnesium stearate at 0.5–1.0% w/w. Twin-screw melt granulation is operated with an L/D of 40:1, barrel zones set between 110–150°C, screw speed 150–250 rpm, product melt temperature 140–160°C, and torque maintained below 50% of drive maximum. The granulate is compressed on a rotary tablet press at 15–25 kN main compression force. Release testing follows USP <711> extended-release dissolution, USP <905> uniformity of dosage units, and ICH Q8(R2) design space verification. Published data for this exact molecule under twin-screw melt granulation is limited; the temperature window must be confirmed by differential scanning calorimetry and thermogravimetric analysis before scale-up. Tablet compression yields an extended-release matrix tablet for oral administration.
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The (S)-(+)-3-hydroxytetrahydrofuran pharma-grade API is released under model code S-HTHF-PG-01 for oral solid applications and S-HTHF-PG-02 for injectable qualification. The product is identified by CAS 86087-23-2, molecular formula C₄H₈O₂, and molecular weight 88.11 g/mol. It is supplied as a clear, colourless to pale yellow liquid with a secondary alcohol and cyclic ether functionality. Steric configuration at the C3 position is controlled by specific optical rotation and chiral chromatographic release tests rather than by density or boiling-point checks alone. For oral tablet, capsule, and granule manufacture, the product is not a direct-compression powder; it is a low-viscosity polar liquid that must be adsorbed, granulated, or otherwise immobilised before dry solid handling. For injectable use, the liquid is transferred under nitrogen into depyrogenated Type I borosilicate vials and tested for bacterial endotoxin. Each batch is released against pharmacopoeial general chapters and ICH impurity guidance, not against a commodity solvent specification. Packaging is supplied in nitrogen-sparged fluorinated high-density polyethylene drums at 1 kg, 5 kg, and 25 kg fill sizes for S-HTHF-PG-01, and in 100 mL or 500 mL depyrogenated Type I glass vials for S-HTHF-PG-02. Package headspace oxygen is controlled below 2.0% v/v at filling.
Release limits for S-HTHF-PG-01 include assay not less than 99.0% by GC-FID area normalisation on a medium-polarity capillary column, with unspecified individual impurities not more than 0.10% and total impurities not more than 1.0%. Enantiomeric purity is controlled at not less than 99.0% enantiomeric excess by chiral gas chromatography using a β-cyclodextrin stationary phase; the corresponding (R)-isomer is controlled at not more than 0.5%. Specific optical rotation at 589 nm and 20 °C is set between +17.0° and +19.0° (c=1.0, methanol). Water by Karl Fischer coulometric titration per Ph. Eur. 2.5.12 or USP <921> is limited to not more than 0.50% in both models. The injectable model S-HTHF-PG-02 adds bacterial endotoxin testing at not more than 0.25 EU/mL per USP <85> or Ph. Eur. 2.6.14. These values are intentionally narrower than technical-grade solvent specifications, where assay may fall below 97.0%, water is often accepted up to 1.0%, and chiral purity may be unstated.
| Parameter | S-HTHF-PG-01 | S-HTHF-PG-02 | Technical grade |
|---|---|---|---|
| Assay, GC-FID area % | ≥99.0% | ≥99.0% | ≥97.0% |
| Enantiomeric excess | ≥99.0% | ≥99.0% | Not specified |
| Specific optical rotation, c=1.0, methanol, 20 °C | +17.0° to +19.0° | +17.0° to +19.0° | Not specified |
| Water, Karl Fischer | ≤0.50% | ≤0.50% | ≤1.0% |
| Residual solvents | ICH Q3C limits, USP <467> | ICH Q3C limits, USP <467> | Limited data |
| Bacterial endotoxin | Not routinely tested | ≤0.25 EU/mL | Not tested |
| Packaging | N₂-sparged fluorinated HDPE drum | Depyrogenated Type I glass vial | Standard HDPE drum |
Because the neat substance is a liquid at ambient temperature, direct compression is not applicable. Solid oral dosage development therefore requires a conversion step, typically adsorption onto a porous excipient or spray congealing. The API is blended with silicified microcrystalline cellulose or colloidal silicon dioxide at 20–30% w/w; low-shear tumble blending at 15–25 rpm for 20–40 min is used. For a 10 L bin blender at 60–70% fill volume, blend uniformity samples taken from 10 positions should show assay relative standard deviation not more than 5.0%. If the final blend is filled into capsules or compressed into tablets, content uniformity is assessed according to USP <905>. If the blend exhibits Carr index above 25 or Hausner ratio above 1.35, slugging or roller compaction is advised before compression. Aqueous wet granulation at high liquid loadings is not recommended because the API partitions into the granulating fluid and can produce non-uniform distribution on drying; alcohol or low-moisture granulation should be evaluated instead.
For granule-based dosage forms, low-moisture granulation is preferred over aqueous wet granulation. When spray granulation is used, the atomised solution of the API with a binder is maintained below 30 °C to avoid volatile loss and to limit acid-catalysed ring opening. The dried premix can be blended with crospovidone at 2–5% w/w; if the liquid-loaded carrier is not adequately dried, tablet hardness may fall below 40 N and friability can exceed 1.0%. Capsule fill weight variation should be monitored with a relative standard deviation not more than 3.0% when using dosator or tamping-pin equipment. These values are process-control signals rather than finished dosage form acceptance criteria; finished product specifications follow the registered dossier. The choice of carrier is not purely a flowability decision. Silicified microcrystalline cellulose reduces oil migration at higher loadings, while colloidal silicon dioxide gives better wetting for granulation but can increase hydrophobicity if total content exceeds 10% w/w. A two-stage addition—50% of the silica premixed with the liquid API, then the remainder added after 10 min—reduces agglomerate formation in a 25 L high-shear mixer.
Injectable use imposes additional controls beyond those used for oral solid manufacture. The S-HTHF-PG-02 model is released with bacterial endotoxin not more than 0.25 EU/mL per USP <85> or Ph. Eur. 2.6.14, and particulate matter is controlled according to USP <787> and Ph. Eur. 2.9.19. The liquid should be filtered through a 0.2 µm PVDF or PTFE membrane before aseptic filling. Terminal sterilisation may be compatible, but the compound is a cyclic ether alcohol; acid-catalysed ring opening can occur at pH below 2.0, and strongly nucleophilic amine buffers should be avoided during formulation development because the product can participate in condensation or displacement reactions that alter the impurity profile. Prolonged contact with uncoated natural rubber closures is not recommended; Type I glass vials with PTFE-laminated septa are used. Extractables and leachables studies follow USP <381> and Ph. Eur. 3.2.9 for elastomeric closure systems.
Storage of bulk liquid is specified at 2–8 °C under nitrogen. Cumulative exposure to ambient air should not exceed 8 h without a nitrogen blanket, because water uptake can exceed the release limit and alter subsequent formulation wetting behaviour. The product is less prone to peroxide formation than unsubstituted tetrahydrofuran, but oxygen exposure during prolonged storage should still be controlled; a peroxide value test is applied if the material is held beyond the assigned retest interval. The (R)-(−)-isomer is controlled as an impurity; racemic 3-hydroxytetrahydrofuran cannot replace the (S)-enantiomer in stereospecific formulation work because its optical rotation is near 0.0° and its pharmacological or synthetic response may differ. Technical-grade 3-hydroxytetrahydrofuran is not a direct substitute in injectable or chiral-specific applications without additional purification, chiral qualification, and microbiological control.
Residual solvents are controlled by headspace gas chromatography according to USP <467> and Ph. Eur. 2.4.24. The synthetic route may involve methanol, tetrahydrofuran, or dichloromethane; ICH Q3C(R8) class 2 limits are applied, with methanol not more than 3000 ppm, tetrahydrofuran not more than 720 ppm, and dichloromethane not more than 600 ppm. Elemental impurities are measured by ICP-MS against ICH Q3D(R2) and USP <232> / <233>. The assigned retest period is 24 months under the recommended storage condition; open containers are not used for injectable manufacture after more than 7 days unless a nitrogen blanket and a water content re-test are performed. The material is incompatible with strong oxidisers, strong mineral acids, and acid chlorides at processing temperatures.
| Quality attribute | Method or standard | Release limit |
|---|---|---|
| Assay | USP <621>, Ph. Eur. 2.2.28 | ≥99.0% |
| Enantiomeric purity | Chiral GC-FID, β-cyclodextrin | ≥99.0% ee |
| Water | Ph. Eur. 2.5.12, USP <921> | ≤0.50% |
| Residual solvents | USP <467>, Ph. Eur. 2.4.24 | ICH Q3C(R8) |
| Elemental impurities | USP <232>, <233>, Ph. Eur. 2.4.20 | ICH Q3D(R2) |
| Bacterial endotoxin, injectable | USP <85>, Ph. Eur. 2.6.14 | ≤0.25 EU/mL |
| Microbial enumeration, non-sterile | USP <61>, <62>, Ph. Eur. 2.6.12, 2.6.13 | TAMC ≤10² CFU/g, TYMC ≤10¹ CFU/g |
Difference from the corresponding (R)-(−)-enantiomer is confirmed by both sign of optical rotation and retention time on chiral GC-FID. The racemic mixture, when deliberately prepared for process troubleshooting, displays no significant rotation and contains both enantiomers in approximately equal proportions; it is not assigned the S-HTHF-PG model code. Material labelled “3-hydroxytetrahydrofuran, 98%” without CAS-specific chiral analysis should be treated as a different product and not mixed with S-HTHF-PG inventory, because even small amounts of the opposite enantiomer can shift the optical rotation outside release limits and invalidate stereospecific process performance.
On manufacturing scale-up, process transfers between a pilot-scale 5 L rotary evaporator and a 500 L glass-lined reactor should be monitored for optical rotation and water content at discharge. Heat history above 60 °C during solvent recovery can increase colour and related substances; therefore, vacuum stripping is performed below 45 °C jacket temperature. Batches that fail water or enantiomeric purity are not reprocessed into the S-HTHF-PG-02 injectable model; rework into technical grade is controlled only when the impurity profile permits. Published data for long-term stability of this compound in specific injectable vehicles is limited; pre-formulation stability studies should therefore include pH, oxygen, and light exposure variables rather than relying on neat API data alone.
