| HS Code | 261704 |
| Product Name | N-(2-Hydroxyethyl)phthalimide Pharma Grade API |
| Synonyms | 2-(2-Hydroxyethyl)isoindoline-1,3-dione; N-(2-Hydroxyethyl)phthalimide; 2-Hydroxyethylphthalimide |
| Cas Registry Number | 3891-07-4 |
| Iupac Name | 2-(2-Hydroxyethyl)isoindoline-1,3-dione |
| Molecular Formula | C10H9NO3 |
| Molecular Weight | 191.18 g/mol |
| Appearance | White to off-white crystalline powder |
| Assay | ≥99.0% (HPLC, on dried basis) |
| Purity | Pharma grade, ≥99.0% |
| Melting Point | 126-128 °C |
| Boiling Point | 347.2 °C at 760 mmHg |
| Flash Point | 163.8 °C |
| Density | 1.377 g/cm³ |
| Refractive Index | 1.601 |
| Solubility | Soluble in methanol, ethanol, acetone, chloroform; slightly soluble in water |
| Loss On Drying | ≤0.5% |
| Residue On Ignition | ≤0.1% |
| Heavy Metals | ≤20 ppm |
| Storage Conditions | Store in a cool, dry, well-ventilated place away from light and moisture |
| Shelf Life | 24 months when stored as directed |
| Packaging | 25 kg net fiber drum with double polyethylene liner |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Pharmaceutical Grade | API grade, GMP manufactured |
| Safety Handling | Irritant; avoid inhalation, ingestion, and skin/eye contact; use appropriate PPE |
As an accredited N-(2-Hydroxyethyl)phthalimide 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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When direct compression is selected for the solid oral dosage route, the low aqueous solubility of N-(2-hydroxyethyl)phthalimide determines the pre-blend particle engineering sequence. A representative tablet core batches the API at 20–45% w/w with microcrystalline cellulose at 50–70% w/w, crospovidone at 2–5% w/w, and magnesium stearate at 0.5–1.5% w/w. The API is sieved through a 500 µm mesh and blended in a bin blender at 15–25 rpm for 15–20 min; powder flow is assessed with a Flodex or ring shear tester, with a target flow function coefficient above 4.0 to sustain rotary press speeds of 25–60 rpm. Tablet compression on a rotary press equipped with B-tooling and 11.0 mm round punches applies 8–18 kN compression force, producing cores with hardness 60–100 N and friability ≤1.0% under USP <1216>. Uniformity of dosage units is verified according to USP <905> and Ph. Eur. 2.9.40, while residual solvent and elemental impurity levels are controlled under ICH Q3C and ICH Q3D. The terminal presentation is an immediate-release film-coated tablet, with the coating step applying 2–4% w/w aqueous film coat at a pan inlet air temperature of 55–75°C and exhaust moisture monitored to prevent imide ring hydrolysis.
Low-moisture operations control the capsule route. A dry-mix formulation containing API at 30–50% w/w, lactose monohydrate at 40–65% w/w, pregelatinized starch at 5–10% w/w, colloidal silicon dioxide at 0.2–1.0% w/w, and sodium stearyl fumarate at 0.5–1.5% w/w is blended in a diffusion mixer at 12–18 rpm and conditioned at ≤40% RH before filling on a dosator capsule machine at 60,000–100,000 capsules/h into size 0 or 1 hard gelatin or HPMC capsules. Fill weight is verified at 5–10 min intervals against ±3% limits, and pre-fill moisture is held at ≤2.0% w/w because higher water activity accelerates hydrolytic opening of the phthalimide ring. Dissolution is tested under USP <711> Apparatus 1 at 100 rpm in 900 mL of pH 6.8 phosphate buffer at 37±0.5°C; stability is assigned under ICH Q1A(R2) at 25°C/60% RH and 40°C/75% RH. The terminal presentation is an immediate-release hard capsule for oral administration.
In high-shear wet granulation trains processing oral granule formulations, moisture control defines the critical process window because the imide ring is susceptible to aqueous hydrolysis. The granulation charge contains API at 10–30% w/w, lactose monohydrate at 50–75% w/w, maize starch at 5–15% w/w, croscarmellose sodium at 2–4% w/w, and povidone K30 at 2–5% w/w; granulating liquid is purified water or a water-isopropanol mixture at 70:30 sprayed at 8–15% w/w of dry charge. A vertical high-shear granulator with impeller speed 150–300 rpm and chopper speed 1,500–3,000 rpm is used, and the wet mass endpoint is monitored by impeller power consumption, with a target torque increase of 15–30% over dry mixing. Drying in a fluid-bed dryer at inlet air temperature 50–65°C continues to a final moisture content of 1.5–2.5% w/w; dried granules are milled through a 1.0–1.6 mm Comil screen. Granule uniformity is tested under Ph. Eur. 2.9.40 and USP <905>, while equipment cleanliness and cross-contamination limits follow 21 CFR 211.67. The granulation pH is maintained between 4.0 and 6.5 because alkaline conditions above pH 7.0 accelerate phthalimide ring hydrolysis and generate ethanolamine-related impurities. The terminal presentation is a single-dose oral granule in a foil-laminate sachet or stick pack, intended for direct administration or reconstitution in water.
| Direct compression oral tablets | USP <905>, USP <1216>, ICH Q3D, ICH Q3C | Uniformity of dosage units, friability, elemental impurities, residual solvents |
| High-speed capsule filling | USP <711>, 21 CFR 211.113, ICH Q1A(R2) | Dissolution, microbiological control, stability |
| High-shear wet granulation | Ph. Eur. 2.9.40, USP <905>, 21 CFR 211.67 | Uniformity of mass of single-dose preparations, content uniformity, equipment cleaning |
| Lyophilised injectable powder | USP <1207>, ISO 14644-1:2015, ICH Q3B | Container closure integrity, aseptic environment, degradation products |
| Ready-to-use injectable solution | USP <788>, USP <790>, ISO 13408-1:2008 | Subvisible and visible particulates, aseptic processing |
| Extended-release matrix tablets | USP <711>, USP <905>, ICH Q2(R1), ICH Q1E | Dissolution, uniformity of dosage units, analytical method validation, extrapolated stability |
Injectable lyophilised presentations require pre-freeze solution design that prevents hydrolysis and collapse. A pre-lyophilisation solution typically contains API at 10–50 mg/mL, mannitol at 20–50 mg/mL as bulking agent, sucrose or trehalose dihydrate at 10–30 mg/mL as cryoprotectant, and a citrate or histidine buffer at 5–20 mM to hold pH at 5.5–7.0. The solution is filtered through 0.22 µm PVDF or PES membranes and filled into USP Type I borosilicate vials under ISO 14644-1:2015 class 5 conditions. Freezing is performed on shelf at -40°C for 3–5 h; primary drying is conducted at -20 to -10°C shelf temperature and chamber pressure 50–100 mTorr for 20–40 h; secondary drying is ramped to 20–30°C for 4–8 h to reduce residual moisture below 1.0% w/w. Published data for this specific configuration is limited, and lyophilisation cycle parameters must be confirmed by freeze-drying microscopy and thermal resistance of the imide-containing solid. Container closure integrity is verified under USP <1207>, and reconstitution time is controlled to ≤2 min with 5–10 mL Water for Injection. Because the imide ring hydrolyses at alkaline pH, reconstitution solutions with pH above 8.0 or containing primary amine buffers are excluded. The terminal presentation is a lyophilised powder in a single-dose vial for intravenous or intramuscular injection after reconstitution.
Only after terminal sterilisation feasibility is ruled out for an injectable presentation does the pH-controlled solution route become viable. A ready-to-use injectable solution containing N-(2-hydroxyethyl)phthalimide API at 5–15 mg/mL is prepared in a water-for-injection vehicle with sodium chloride 0.9% w/v for isotonicity and possibly PEG 300 10–30% v/v as a cosolvent, held at pH 5.0–6.5 with a 10–25 mM acetate or citrate buffer. The manufacturing train includes cold dissolution at 15–25°C, nitrogen blanketing, and filtration through 0.22 µm sterilising-grade filters. If terminal steam sterilisation is applied at 121°C for 15 min, pre-validation must demonstrate that phthalimide ring degradation products remain within ICH Q3B reporting thresholds; when thermolysis exceeds the threshold, aseptic processing under ISO 13408-1:2008 is used instead. Particulate matter is assessed per USP <788> and subvisible particle counts must meet ≥10 µm and ≥25 µm limits; visible particulates are controlled under USP <790>. The terminal presentation is a sterile injectable solution in single-dose vials or ampoules, with an in-use stability hold not exceeding 24 h at 2–8°C.
Extended-release matrix tablets containing the API use hypromellose grade selection to modulate release. The matrix core comprises API at 15–35% w/w, hypromellose K4M or K100M at 20–40% w/w, microcrystalline cellulose at 20–40% w/w, and magnesium stearate at 0.5–1.0% w/w; the ratio of API to polymer is adjusted so that polymer percolation occurs above 20% w/w. Roller compaction is used when direct compression lacks the required bulk density: ribbon density is maintained at 0.8–1.2 g/cm³, followed by milling through a 0.8–1.2 mm screen. Tablets are compressed on a rotary press at 12–25 kN, with hardness 80–150 N and friability ≤1.0% under USP <1216>. Dissolution is assessed using USP <711> Apparatus 1 or 2 at 37±0.5°C, with acceptance ranges such as NLT 60% released by 8 h and NLT 80% by 12 h in pH 6.8 phosphate buffer; method parameters are validated per ICH Q2(R1). Uniformity of dosage units follows USP <905>, and stability under ICH Q1E is evaluated at 25°C/60% RH and 40°C/75% RH for 6–12 months. The matrix is incompatible with strongly alkaline additives because pH above 7.0 accelerates imide hydrolysis and shifts release to pore-mediated erosion. The terminal presentation is an extended-release film-coated tablet.
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N-(2-Hydroxyethyl)phthalimide Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is controlled as a neutral, non-salt crystalline substituted imide with CAS 3891-07-4, molecular formula C10H9NO3, and molar mass 191.18 g/mol. The product is supplied as two physical models: Model A micronized, with d90 ≤ 20 µm by laser diffraction, and Model B granular, with d90 100–250 µm. Both models are released against the same chemical purity envelope and are intended for direct compression, dry granulation, capsule filling, oral liquid preparation, and sterile injectable processing. The product is not supplied as a sterile API; terminal sterilization or aseptic processing of the formulated dosage form is required for injectable use. The principal distinction from technical-grade N-(2-hydroxyethyl)phthalimide is the controlled impurity profile, residual solvent limits, elemental impurity testing, and bioburden/endotoxin control appropriate to the route of administration.
The molecule is produced by condensation of phthalic anhydride with ethanolamine, and the resulting crystalline solid retains process-related impurities that must be removed and controlled. Residual phthalic anhydride, ethanolamine, unsubstituted phthalimide, and ring-opened phthalamic acid derivatives are monitored by HPLC. Pharmaceutical release testing is performed at 25 ± 2 °C and 60 ± 5% RH. Because no harmonized individual monograph for this molecule currently appears in USP, Ph. Eur., or JP, the specification matrix is assembled from general chapter methodologies and ICH guidance; this does not reduce the finished pharmaceutical product obligation to qualify its own control strategy.
Technical-grade material is typically supplied with assay 95–98% by non-compendial titration or gas chromatography, while the pharma-grade release limit is assay 98.0–102.0% by HPLC against a qualified reference standard. The more important separation is the impurity profile. Technical material may retain residual phthalic anhydride, ethanolamine, unsubstituted phthalimide, toluene or dimethylformamide residues, and elemental impurities from non-dedicated equipment. Pharma grade applies ICH Q3D Option 1 elemental impurity limits by USP <233> ICP-MS, residual solvent limits under USP <467>, and related substances reporting with unspecified impurities limited to 0.10% and total impurities limited to 1.0%. For injectable-grade release, bacterial endotoxin is controlled at ≤ 2.5 EU/g by USP <85>; this test is not normally performed on technical material.
The substitution with a 2-hydroxyethyl side chain also differentiates this molecule from unsubstituted phthalimide in crystal packing and processing. The pendant hydroxyl group increases polar surface area, alters wetting in aqueous media, and lowers the melting point to approximately 126–128 °C, compared with unsubstituted phthalimide near 238 °C. This means the product is not a high-melting stable imide and should not be held in strongly alkaline aqueous granulating fluid because phthalimide ring opening to the corresponding phthalamic acid is a known hydrolytic pathway.
The release matrix used for batch certification is shown below. The material is tested after vacuum drying to loss on drying ≤ 0.5%. If the batch is intended for sterile injectable manufacture, additional bioburden and endotoxin samples are drawn.
| Attribute | Acceptance limit | Reference method |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Identification | FTIR spectrum concordant with reference; retention time matches standard | Ph. Eur. 2.2.24; USP <197> |
| Assay on dried basis | 98.0–102.0% | HPLC, USP <621> |
| Total related substances | ≤ 1.0% | HPLC area normalization |
| Unspecified impurity | ≤ 0.10% | HPLC area normalization |
| Loss on drying | ≤ 0.5% | USP <731> |
| Sulfated ash | ≤ 0.1% | Ph. Eur. 2.4.14 |
| Elemental impurities | ICH Q3D Option 1 limits | USP <233> ICP-MS |
| Melting range | 126–128 °C | Ph. Eur. 2.2.14 |
| Residual solvents | Class 1 absent; Class 2 within USP <467> options | USP <467> |
| Microbial limits | TAMC ≤ 100 CFU/g; TYMC ≤ 10 CFU/g; E. coli absent | USP <61>/<62> |
| Bacterial endotoxins, injectable | ≤ 2.5 EU/g | USP <85>; Ph. Eur. 2.6.14 |
| Particle size | Model A d90 ≤ 20 µm; Model B d90 100–250 µm | ISO 13320-1:2020 |
When the API is received for solid oral dosage development, the two physical models are not interchangeable without recomputing the operating window. Model A tends to form cohesive powders and is generally unsuitable for direct compression without forced feeding. Model B is preferred for ensembled powder flow and capsule filling; it is controlled to maintain a Hausner ratio ≤ 1.35 by USP <616> Method II. Powder flow classification is reported according to USP <1174>.
| Parameter | Model A micronized | Model B granular |
|---|---|---|
| d90 by laser diffraction | ≤ 20 µm | 100–250 µm |
| Bulk density | 0.30–0.45 g/cm³ | 0.40–0.52 g/cm³ |
| Hausner ratio | 1.30–1.45 | ≤ 1.35 |
| Flow classification | Cohesive | Free-flowing |
| Preferred unit operation | Wet granulation, suspension | Direct compression, capsule filling |
| Principal failure mode | Hopper segregation, punch sticking | Reduced surface area, dissolution slowdown |
Model A is specified to increase specific surface area for dissolution rate improvement, but this benefit is only realized when the formulation prevents agglomeration. In a high-shear wet granulator, impeller tip speed is typically maintained at 5–8 m/s with chopper speed 1500–2500 rpm for a 65 L bowl. Binder addition rate below 0.2 kg/min reduces overwetting; endpoint is determined by torque and power consumption rather than by fixed time. After fluid-bed drying with inlet air at 55–65 °C, granule moisture is controlled to 0.3–0.8%. Moisture above 1.0% can alter compaction behavior and should be investigated by loss on drying and near-infrared moisture balance.
Model B is the direct-compression and encapsulation model. Its bulk density control range is 0.40–0.52 g/cm³, tapped density 0.50–0.65 g/cm³, and Hausner ratio ≤ 1.35. On rotary tablet presses, a forced feeder is recommended. Compression force from 10–25 kN on B-tooling usually produces coherent tablets, but ejection force and capping must be monitored because fines can increase die-wall friction. If the fraction passing 75 µm exceeds 30% of the blend, segregation is observed at compression speeds above 50 rpm on a 16-station press. Adding 0.5–1.0% colloidal silicon dioxide and 0.5–1.5% magnesium stearate improves flow but can reduce tensile strength if over-lubricated. Lubricant mixing time should be limited to 3–5 min in a bin blender at 10–15 rpm.
Dry granulation by roller compaction is an alternative when aqueous binder is avoided. For Model B, roll pressure 5–10 MPa, roll gap 1–2 mm, and screen size 0.8–1.0 mm produce granules suitable for capsule filling. Recycle fines should be limited to 30% or less; higher recycle fractions increase work-hardened material and reduce compactibility. Compact tensile strength is measured according to USP <1217>. If tablet tensile strength drops below 1.5 MPa, the granulation endpoint must be adjusted. Intrinsic dissolution rate by USP <1087> rotating disk should be part of the product development report because published data for this specific compound is limited.
For hard gelatin and HPMC capsules, fill weight control depends on bulk density and granule size distribution. The Model B material with Carr index ≤ 18 generally performs on dosator and dosing-disk machines. If plug formation occurs, pregelatinized starch at 5–10% reduces sensitivity to machine speed. Finished dosage form content uniformity is assessed by USP <905>; acceptance value ≤ 15.0 is applied unless the registration file specifies tighter limits.
Parenteral formulations require a distinct grade with bioburden, endotoxin, and particulate matter control. The solid API is not sterile upon receipt; the finished dosage form is sterilized by moist heat per ISO 17665-1:2006 or by filtration through a 0.22 µm validated membrane. The neutral molecule has no ionizable salt form; pH adjustment with citrate or phosphate buffer to 6.0–7.4 is typical. If the target concentration exceeds aqueous solubility at that pH, a cosolvent system such as PEG 300 or propylene glycol may be used; however, published data for this specific molecule in mixed cosolvent systems is limited, so solubility must be measured in the selected vehicle.
Hydrolysis of the imide ring is pH-dependent. Batch developers should avoid holding solutions above pH 8.0 at temperatures above 40 °C. Terminal sterilization at 121 °C for 15 min may generate process impurities; assay and related substances must be rechecked after the sterilization cycle. The product is not a lyophilized salt. If freeze-drying is used, bulking agents such as mannitol or trehalose at 4–5% w/v are common. Primary drying at shelf temperature -20 °C to -10 °C and chamber pressure 50–150 µbar avoids collapse, but this must be confirmed by thermal characterization of the formulation.
Oral liquid solutions face similar constraints. A buffer below pH 8.0 is used, and alcohol-free vehicles may require cyclodextrin or cosolvent. The product is not classified as highly soluble; dissolution in simulated gastric fluid should be measured according to USP <711>, and a method providing sink conditions may require surfactant. Because the neutral molecule has no counterion pH shift, it does not introduce chloride, mesylate, or citrate burden into infusion solutions; this is a meaningful difference from salt-form APIs.
In relation to other substituted imides, the important differences are melting point, polarity, and residual solvent profile. N-methylphthalimide lacks the terminal hydroxyl, is less polar, and may exhibit different compaction and solubility characteristics. Potassium phthalimide is a salt and is not generally interchangeable with the neutral N-(2-Hydroxyethyl)phthalimide molecule in non-aqueous processing or in formulations where the counterion would alter tonicity and buffer capacity. The pharma-grade product supplies a crystalline, single-molecular entity without counterion pH burden and can be controlled for both oral and injectable routes; however, the formulator must account for its pH-dependent ring stability, limited aqueous solubility, and particle-size-dependent dissolution. Published data for this specific compound in some configurations, such as lyophilized injectable formulations, remains limited, so development studies should be conducted with the exact physical model used in manufacture.
