| HS Code | 548519 |
| Productname | 2P (2-Pyrrolidone) Pharma Grade API |
| Chemicalname | 2-Pyrrolidone |
| Synonyms | 2-Pyrrolidinone; alpha-Pyrrolidone; Butyrolactam; 2-Oxopyrrolidine |
| Casnumber | 616-45-5 |
| Molecularformula | C4H7NO |
| Molecularweight | 85.10 g/mol |
| Appearance | Colorless to pale yellow liquid or low-melting solid |
| Purityassay | >=99.0% (pharma grade) |
| Grade | Pharma Grade / API |
| Dosageforms | Tablet / Capsule / Granule / Injection |
| Routeofadministration | Oral & Injectable |
| Solubility | Miscible with water, ethanol, ether, chloroform |
| Meltingpoint | 24-25 °C |
| Boilingpoint | 245 °C |
| Density | 1.116 g/cm3 at 25 °C |
| Refractiveindex | 1.487 at 20 °C |
| Ph | Neutral to slightly alkaline (aqueous solution) |
| Storage | Store in cool, dry, well-ventilated area; keep container tightly closed; away from oxidizers |
| Packaging | 25 kg, 200 kg drums or as per customer requirement |
| Shelflife | 24 months when stored properly |
As an accredited 2P (2-Pyrrolidone) 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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Immediate-release tablet manufacturing with 2-Pyrrolidone Pharma Grade as a granulation fluid component has been scaled in high-shear granulators from 25 L to 600 L bowl volume. The liquid is not dry-blended; a 1:4 2-Pyrrolidone–purified water granulation vehicle is sprayed through a 1.2 mm binary nozzle at 0.5–1.5 bar atomizing air and a spray rate of 0.3–0.8 kg/min per 100 kg dry mass. The main impeller tip speed is held at 2–6 m/s, with the chopper at 1000–2000 rpm, until impeller power reaches 65–80% of the maximum load recorded for the batch. Addition ratio in the wet mass is 1.8–3.6% w/w of the dry blend for microcrystalline cellulose-based formulations; for high-dose tablets containing 500–1000 mg active per unit, the upper addition ratio is capped at 4.5% w/w because excess solvent retention after drying increases tablet hardness non-uniformity. Pre-drying of microcrystalline cellulose and crospovidone at 40°C for 12 h is required when ambient relative humidity exceeds 60% because the 2-Pyrrolidone–water granulation fluid binds preferentially to free moisture, shifting granule size distribution. Wet granules are discharged through a 6–10 mm screen and dried in a vacuum dryer at 45 ± 5°C and 10–20 kPa until loss on drying by USP <731> is 1.5–2.5% w/w. Residual 2-Pyrrolidone is determined by headspace gas chromatography per USP <467> with a limit of NMT 0.5% w/w; production-scale drying curves show that residual solvent falls below this limit only when granule bed temperature stays above 40°C for at least 30 min after endpoint moisture is reached. Compression on a 27-station rotary press uses 25–30 kN main compression and 8–12 kN pre-compression at 30–60 rpm turret speed; capping at tablet hardness above 15 kp is prevented by adding 0.5–1.0% w/w magnesium stearate after granulation. Disintegration is tested by USP <701> in 900 mL water at 37 ± 2°C; film-coated immediate-release tablets require disintegration NMT 30 min. Dissolution by USP <711> Apparatus II uses 50 rpm, 900 mL pH 6.8 phosphate buffer, with an immediate-release acceptance of Q = 80% at 30 min. Industrial compliance is maintained under 21 CFR 210/211 cGMP, with batch release including content uniformity per USP <905>. Terminal finished product type: film-coated immediate-release tablets.
Because shell compatibility and water activity, not active solubility alone, determine the feasible 2-Pyrrolidone loading in liquid-filled hard capsules, hypromellose capsule shells are specified when the fill contains 10–20% w/w 2-Pyrrolidone in a water-miscible carrier system. Gelatin shells plasticize and pit after 14 days at 40°C/75% RH when the fill water activity exceeds 0.35. Addition ratio in the fill mass is 12–18% w/w for BCS II weak acids; above 20% w/w, published data for 2-Pyrrolidone-rich HPMC capsule fills remain limited, and 3-month ICH Q1A (R2) stability data must be generated before use in regulatory submissions. The fill preparation process uses a jacketed vacuum high-shear mixer at 800–1500 rpm and 25–35°C, with deaeration under −0.08 MPa until bubble-free. Fill viscosity is held below 200 mPa·s at 25°C to allow consistent piston-type capsule filling with 0.5–2.0 mL dosing nozzles and fill accuracy ±2.0% of target weight. Capsule sealing uses HPMC-based banding solution at 55–60°C, followed by infrared drying at 40–50°C for 1–2 min. Finished product type: HPMC liquid-filled hard capsules. Batch release testing includes dissolution by USP <711> with stainless-steel sinkers, content uniformity by USP <905>, microbial enumeration by USP <61>/<62>, and water activity by dew point analyzer. The operational boundary is explicit: 2-Pyrrolidone-rich fills should not be combined with gelatin capsule shells unless fill water activity is kept at or below 0.20 and sealed capsules are stored below 25°C/60% RH; otherwise shell distortion is observed within 30 days. Residual 2-Pyrrolidone after fill preparation is confirmed by USP <467> to be NMT 0.5% w/w in the finished capsule matrix.
For sachet-dispensed oral granules, top-spray fluid-bed granulation in a 30–500 L apparatus equipped with a 10–14 mm spray nozzle is used with 2-Pyrrolidone Pharma Grade diluted 1:5 with purified water and sprayed at 8–15 g/min per kg dry solids. Inlet air temperature is 55–70°C, product bed temperature is 32–38°C, and inlet air dew point is 5–8°C to prevent hygroscopic agglomeration. Addition ratio is 0.8–2.2% w/w of the final dry granulate. Spraying is stopped when pressure drop across the granule bed increases by 8–15% from the dry-mix baseline; endpoint is confirmed by near-infrared moisture content of 2.0–3.5% w/w. Drying continues at 60–65°C until loss on drying by USP <731> is NMT 2.0% w/w. Residual 2-Pyrrolidone after drying is controlled below 0.3% w/w by gas chromatography per USP <467>; if inlet air dew point exceeds 8°C, granule agglomeration variability at the outlet can shift the residual solvent result to 0.6–0.8% w/w. Granule porosity is assessed by bulk and tapped density per USP <616> Method I and II; Carr’s index of 15–25% is required for consistent filling into stick packs at 50–60 packs/min. Finished granules are filled at 1.0–5.0 g per sachet on a vertical form-fill-seal machine with nitrogen flushing to residual oxygen NMT 2.0%. Terminal finished product types: granules for oral suspension in sachets and granules for direct oral administration. Compliance standards include 21 CFR 210/211, USP <785> for osmometry? No, osmolality is USP <785>; dissolution testing applies only after reconstitution as per USP <711>.
In continuous lines, a co-rotating twin-screw granulator with 16 mm screw diameter and 40:1 L/D ratio receives 2-Pyrrolidone Pharma Grade by lateral liquid injection at barrel zone 4 of 10. Powder feed is 2–10 kg/h, screw speed is 150–400 rpm, and solvent feed is metered at 2.3–4.1% w/w of the powder feed rate. Barrel temperature is maintained at 25–35°C to prevent solvent evaporation along the first 3 zones; specific mechanical energy measured from torque is 5–15 kJ/kg. The wet mass exits through a 1.5 mm die plate and is transferred to a segmented fluid-bed dryer operated at 55–70°C inlet air; residual 2-Pyrrolidone after drying is held below 0.3% w/w, and granule fraction between 125 µm and 850 µm is fixed at NLT 70% of total mass. Residence time distribution is measured by a near-infrared tracer at 1550–1650 nm; variance is held below 0.1 to ensure blend homogeneity. Addition ratio at 2.3–4.1% w/w is narrower than batch high-shear processing because short residence time and low shear mechanical energy demand lower granulation liquid levels. This route is adopted for high-potency tablet and granule intermediate manufacturing where batch-to-batch granule density variation must remain within ±2.0% of target density. Compliance is anchored to 21 CFR 210/211 and process analytical technology control under ICH Q8(R2) design-space verification. Tablet breaking force is tested by USP <1217>, and dissolution is tested by USP <711>. Terminal finished product types: immediate-release tablets or granules for compressed tablets.
| Production route | 2-Pyrrolidone addition ratio | Critical process limit | Primary test method |
|---|---|---|---|
| High-shear wet granulation tablet | 1.8–3.6% w/w dry blend | Residual after drying NMT 0.5% w/w | USP <467>, USP <711> |
| Liquid-filled HPMC capsule | 12–18% w/w fill mass | Water activity NMT 0.35 | USP <711>, USP <905> |
| Top-spray fluid-bed granule | 0.8–2.2% w/w granulate | Loss on drying NMT 2.0% w/w | USP <731>, USP <616> |
| Twin-screw continuous granulation | 2.3–4.1% w/w powder feed | Granule yield 125–850 µm NLT 70% | ICH Q8(R2), USP <467> |
Parenteral use of 2-Pyrrolidone Pharma Grade is restricted to vehicle feasibility studies because no harmonized monograph sets a universal concentration ceiling. The compound is miscible with water, and aqueous injection development uses 0.5–5.0% w/v to maintain solubility of poorly water-soluble actives before pH adjustment. The vehicle is prepared in a jacketed glass-lined vessel at 20–25°C under nitrogen purging at 0.2–0.5 L/min, adjusted to pH 4.0–7.4 with carbon dioxide or sodium hydroxide, and filtered through a 0.22 µm PVDF sterile filter. Addition ratios above 5.0% w/v require local tolerance and systemic toxicity data; no compendial limit replaces this toxicological qualification. Terminal steam sterilization at 121°C for 15 min is avoided unless forced degradation shows hydrolytic ring opening to 4-aminobutyric acid below 0.10% w/w; aseptic filtration is the preferred manufacturing route. For small-volume injectables not exceeding 100 mL, particulate matter per USP <788> Method 1 is controlled at NMT 6000 particles per container at ≥10 µm and NMT 600 particles per container at ≥25 µm. Bacterial endotoxins per USP <85> are controlled at NMT 0.5 EU/mg for intravenous administration; for intrathecal or high-risk routes, lower limits apply. Osmolality is adjusted with sodium chloride to 270–320 mOsm/kg, measured by freezing-point depression. Lyophilization is applied when aqueous stability is insufficient: primary drying at −20°C to −10°C shelf temperature for 6–12 h, secondary drying at 20°C for 2–4 h. Collapse above −18°C is a documented batch failure mode if the eutectic temperature has not been mapped; 2-Pyrrolidone-containing formulations may remain amorphous and require conservative primary drying. Terminal finished product types: aqueous injection for parenteral administration and lyophilized cake for reconstitution. Compliance is maintained under 21 CFR 211, USP <1>, and Ph. Eur. 5.1.1.
| Route | Critical quality attribute | Pharmacopoeial code | Operational limit |
|---|---|---|---|
| Immediate-release tablet | Dissolution | USP <711> | 50 rpm, pH 6.8, Q=80% at 30 min |
| Immediate-release tablet | Friability | USP <1216> | NMT 1.0% weight loss |
| Liquid-filled HPMC capsule | Content uniformity | USP <905> | AV ≤15 |
| Oral granule | Bulk/tapped density | USP <616> | Carr’s index 15–25% |
| Injection, ≤100 mL | Particulate matter | USP <788> | ≥10 µm: NMT 6000/container; ≥25 µm: NMT 600/container |
| Injection, IV route | Bacterial endotoxin | USP <85> | NMT 0.5 EU/mg |
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2P (2-Pyrrolidone) Pharma Grade API is a high-purity lactam solvent and formulation processing agent released under grade designation 2P-PG-API for tablet, capsule, granule, oral liquid, and injectable manufacture. The substance is pyrrolidin-2-one, CAS 616-45-5, molecular formula C4H7NO, and molecular weight 85.10 g·mol⁻¹. At 25 °C the product appears as a clear, colorless to pale yellow liquid; at or below approximately 25 °C it may solidify into a white low-melting crystalline mass. The injectable grade differs from the oral grade by bacterial endotoxin and particulate matter certification; the oral grade is released with a broader microbial enumeration specification but the same assay, water, peroxide, and residue-on-ignition profile.
The product is not a generic industrial solvent. Its pharma-grade specification controls water to ≤0.20% w/w by Ph. Eur. 2.5.12, peroxides to ≤20 meq·kg⁻¹ by Ph. Eur. 2.5.5, residue on ignition to ≤0.05% w/w by Ph. Eur. 2.4.14, and chloride/sulfate to ≤50 mg·kg⁻¹ by Ph. Eur. 2.3.1 and 2.3.2. Density at 25 °C is approximately 1.11 g·cm⁻³, viscosity is approximately 13.3 mPa·s at 25 °C, and the product is hygroscopic. Dispensing should be performed under nitrogen or dry air with a dew point below −20 °C if suite humidity exceeds 60% RH. Elemental impurities follow ICH Q3D Option 2A, covering Class 1 and Class 2A elements against oral and parenteral permitted daily exposures.
| Parameter | Analytical method | Release limit |
|---|---|---|
| Appearance | Visual inspection against white background | Clear, colorless to pale-yellow liquid at 25 °C; no visible particles |
| Assay | GC-FID area percent | ≥99.5% |
| Water | Ph. Eur. 2.5.12 | ≤0.20% w/w |
| Residue on ignition | Ph. Eur. 2.4.14 | ≤0.05% w/w |
| Peroxide value | Ph. Eur. 2.5.5 | ≤20 meq·kg⁻¹ |
| Chloride | Ph. Eur. 2.3.1 | ≤50 mg·kg⁻¹ |
| Sulfate | Ph. Eur. 2.3.2 | ≤50 mg·kg⁻¹ |
| Bacterial endotoxins, injectable grade | Ph. Eur. 2.6.14 | ≤0.50 EU·mg⁻¹ |
| Microbial enumeration | Ph. Eur. 2.6.12, 2.6.13 | TAMC ≤100 CFU·g⁻¹, TYMC ≤10 CFU·g⁻¹, E. coli absent |
| Elemental impurities | ICH Q3D Option 2A | Class 1 and Class 2A oral and parenteral limits |
In tablet and capsule development, the material functions mainly as a high-boiling granulation solvent, dissolution-enhancing co-solvent, and solid-dispersion processing aid, not as a polymeric binder or disintegrant. The small molecule contains a secondary amide N-H group, which contributes hydrogen-bond donor capacity and distinguishes it from N-methyl-2-pyrrolidone. Formulation development therefore treats 2P-PG-API as a process solvent that must be substantially removed, not as a matrix-forming excipient.
The specification for 2P-PG-API is intended to support downstream process validation, not to replace it. For tablet and capsule products, dissolution and content uniformity are verified by Ph. Eur. 2.9.3 and 2.9.6 or USP <711> and USP <905>. Wet granulation with 2P-PG-API produces a different drying curve than ethanol or water; process analytical technology such as near-infrared or headspace GC is used to distinguish residual organic solvent from water because Karl Fischer alone does not quantify 2-pyrrolidone.
In high-shear wet granulation, 2P-PG-API is metered into a powder bed as a liquid binder solvent. Its viscosity is approximately 13.3 mPa·s at 25 °C, significantly higher than water and N-methyl-2-pyrrolidone, and its boiling point is approximately 245 °C at 760 mmHg. These properties create the main process constraint: liquid bridges formed during wet massing are robust, but evaporative removal is slow. A high-shear granulator with impeller tip speed 2.0–6.0 m·s⁻¹ and chopper speed 1500–3000 min⁻¹ is used to distribute the solvent. The endpoint is based on power draw and torque rather than volume addition; over-wetting leads to granule size growth beyond 1000 µm and later tablet capping, while under-wetting creates fines with poor compressibility.
Drying is rate-limited by the low vapor pressure of 2P. Conventional tray drying at 50–60 °C and ambient pressure often leaves residual solvent above the specification for tablet cores because the solvent evaporates more slowly than water. Production-scale drying therefore requires vacuum tray dryers or rotary vacuum dryers with absolute pressure below 30 kPa and wall temperature controlled at 50–60 °C. Fluid-bed dryers may be used with inlet air temperature 60–70 °C, dew point below −20 °C, and exhaust humidity monitoring to avoid recondensation in bag filters. The drying endpoint is not time-fixed; it is determined by GC-HS or GC-MS against a validated residual solvent limit for the drug product. Because the harmonized ICH Q3C list does not assign a publicly harmonized class to every lactam solvent, the residual solvent limit for 2-pyrrolidone is route-dependent and should be derived from toxicological data, regional submission guidance, and cleaning validation results. Published production-scale drying data for this exact configuration is limited; therefore pilot-scale dryer qualification should precede full-scale technical transfer.
Granule milling after vacuum drying is a second thermal risk. The low melting point of 2-pyrrolidone means that frictional heat in an oscillating or conical mill can raise the milled material above 25 °C, forming a partially fused surface layer that reduces yield. Mills with cooled rotors or intermittent operation are used for formulations containing this solvent; the target granule size for tableting is typically a D50 of 150–350 µm, with particle size distribution measured by sieve analysis per Ph. Eur. 2.9.12. Compaction profiles are evaluated on single-station and rotary tablet presses; compressibility and ejection force are recorded because trace residual 2P can act as a plasticizer in polymer-containing granulations.
For capsule products, 2P-PG-API may be part of a liquid-fill matrix or used as a wet granulation solvent prior to encapsulation. Liquid-fill capsule equipment must maintain contact surfaces above 25 °C to avoid solidification in transfer lines. Hard gelatin and HPMC capsule shells exposed to residual 2-pyrrolidone can show moisture-dependent shell softening or deformation; stability studies at ICH Q1A conditions 40 °C / 75% RH are used to verify shell integrity and disintegration by Ph. Eur. 2.9.1. For dry-filled capsules produced by granulation, the dried granule is blended with extragranular excipients and filled on an automatic capsule filler; residual solvent must be below the established limit before filling to avoid headspace solvent build-up in sealed packaging.
In oral liquid formulations, 2P-PG-API is combined with purified water, buffers, and sweeteners. The material is miscible with aqueous phases and can reduce precipitation of poorly water-soluble active pharmaceutical ingredients. Solution clarity is controlled by Ph. Eur. 2.2.1, color by Ph. Eur. 2.2.2, and osmolality by Ph. Eur. 2.2.35. At concentrations above 10% w/v, osmolality and palatability require formulation adjustment; the solvent contributes to the overall osmolar load and may require sodium chloride or glycerin modification to meet oral rehydration or pediatric acceptability criteria.
For injectable grade 2P-PG-API, the release specification includes bacterial endotoxins ≤0.50 EU·mg⁻¹ by Ph. Eur. 2.6.14. The material is not supplied sterile; aseptic processing of the final formulation is required. A 20% w/v aqueous solution is filtered through 0.22 µm PVDF or PES membrane filters prior to filling. Filter compatibility studies are mandatory because 2-pyrrolidone may extract additives from mixed cellulose esters; PVDF and PES membranes are tested for extractables and particulate shedding before process qualification.
pH and hydrolysis are principal injection risks. The secondary amide ring is stable near neutral pH but undergoes hydrolytic ring opening at pH below 2 or above 10 at elevated temperature, forming 4-aminobutyric acid. Terminal sterilization at 121 °C for 15 min is possible only when the formulation pH and buffer capacity maintain the drug product within the stability window. Stability-indicating UPLC or LC-MS methods monitor 4-aminobutyric acid and total related substances. Packaged injectables require container closure compatibility; sulfur-cured elastomeric closures may release leachables into a high-2P formulation, so fluoro-polymer-coated closures are used for long-term storage. Glass Type I vials per Ph. Eur. 3.2.1 are suitable if the fill volume and headspace are controlled.
Compared with N-methyl-2-pyrrolidone, 2-pyrrolidone has a secondary amide N-H and a different hydrogen-bond profile. NMP has lower viscosity and a lower boiling point but carries region-specific toxicological restrictions such that it is not a direct substitute in injectable formulations. Compared with povidone K30, 2P is a molecular solvent, not a polymeric binder; it does not provide tablet hardness or disintegration control. Compared with propylene glycol and glycerin, 2P may improve solubilization of certain poorly water-soluble APIs but has a higher boiling point and slower evaporative removal. Published comparative solubility data for specific APIs in this grade is limited; formulation-specific equilibrium solubility should be measured by the shake-flask method with UPLC or HPLC analysis before committing to a commercial process.
| Product | State at 25 °C | Primary function in solid and injectable dosage forms | Key process risk |
|---|---|---|---|
| 2P Pharma Grade | liquid/low-melting solid | granulation solvent, solubilizer, co-solvent | residual solvent removal, low melting point |
| NMP | liquid | industrial pharmaceutical solvent | toxicological restrictions, skin penetration |
| Povidone K30 | solid powder | binder, dissolution aid | granule hardening, slower disintegration at high levels |
Operational boundaries are defined by the balance between solvency and vapor-pressure constraints. 2P-PG-API is not suited to processes requiring rapid air-drying at atmospheric pressure, nor to direct compression because it is a viscous liquid at processing temperatures. It is incompatible with strong oxidizing agents, strong acids, strong bases, and sulfur-based curative systems that can degrade or discolor. Bulk storage should use sealed stainless steel or fluoropolymer-lined containers under inert gas; carbon steel contact is avoided due to moisture uptake and iron discoloration risk. At relative humidity above 60%, handling without dry-air protection increases water content and may shift the solid-liquid boundary. Long-term storage data beyond 36 months in unopened containers is limited; retest intervals are assigned from real-time stability studies according to ICH Q1A.
Equipment cleaning after 2P-PG-API use requires high-temperature or vacuum-assisted cleaning because the solvent has low volatility and strong solvency for organic residues. Clean-in-place circuits are operated with purified water above 60 °C and validated under 21 CFR 211.67; residual solvent on product-contact surfaces is monitored by swab or rinse sampling with GC-MS. Visual inspection alone is insufficient because a thin film of 2-pyrrolidone may be transparent. Cleaning validation limits are set from the next-product carry-over calculation and the therapeutic daily dose of the next manufactured product.
