1-Methyl-5-(P-Toluoyl)-2-Pyrroleacetic Acid
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HS Code |
799456 |
| Chemical Formula | C15H15NO3 |
| Molar Mass | 257.284 g/mol |
| Physical State At Room Temperature | Solid |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, acetone |
| Acidity | Weakly acidic due to the carboxylic acid group |
As an accredited 1-Methyl-5-(P-Toluoyl)-2-Pyrroleacetic Acid factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram pack of 1 - Methyl - 5 - (P - Toluoyl) - 2 - Pyrroleacetic Acid in sealed chemical - grade pouch. |
| Shipping | 1 - Methyl - 5 - (P - Toluoyl) - 2 - Pyrroleacetic Acid is shipped in properly sealed containers, compliant with chemical transportation regulations. Shipment ensures protection from external factors to maintain product integrity during transit. |
| Storage | 1 - Methyl - 5 - (P - Toluoyl)-2 - Pyrroleacetic Acid should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contact with air, which could potentially lead to degradation. Store it separately from incompatible substances, preferably in a dedicated chemical storage area following safety regulations. |
Conversion of 1-methyl-5-(p-toluoyl)-2-pyrroleacetic acid into the pharmacopeial sodium salt dihydrate proceeds in an aqueous system under nitrogen atmosphere at 20±5°C. The free acid is suspended in delonised water at a ratio of 5–7 L/kg and neutralized with 10N sodium hydroxide solution dosed over 45–60 minutes to a molar endpoint of 1.00±0.02 relative to the acid, while maintaining the pH at 10.0–10.5 to suppress pyrrole ring oxidation. The stoichiometric alkali demand equates to approximately 0.28 kg NaOH per kilogram of acid on an anhydrous basis. The resulting solution is treated with activated carbon (0.5% w/w) at 50°C for 30 minutes, filtered through a 0.45 µm membrane, and then subjected to a controlled linear cooling ramp from 50°C to 5°C at −0.3°C/min to precipitate tolmetin sodium dihydrate. The crystal slurry is centrifuged in a basket centrifuge (Rousselet Robatel RC-1200) at a washing ratio of 2×1 L/kg cold purified water, and the wet cake is vacuum-dried in a conical dryer (Biazzi) at 45°C and −0.95 bar until a loss on drying of 1.5–2.5% is reached. The final milled product meets the USP monograph for Tolmetin Sodium, with a d90 typically below 100 µm and residual solvent limits per ICH Q3C. Process compliance is framed by ICH Q7 §12.1 for API manufacturing, EU GMP Part II, and the specific identity and purity tests of USP 43–NF 38. Terminal product: Tolmetin Sodium Dihydrate API suitable for solid oral dosage forms.When does high-shear wet granulation become mandatory over direct compression for this highly water-soluble sodium salt?Although tolmetin sodium dihydrate exhibits rapid aqueous dissolution, its needle-like crystal habit and high unit dose (200–400 mg) create flow and compressibility deficiencies that render direct compression unreliable at press speeds exceeding 60,000 tablets per hour. High-shear wet granulation is therefore employed to densify the primary particles and embed intergranular binder bridges. A representative 200 mg tablet core is formulated with 57.1% w/w tolmetin sodium dihydrate (equivalent to 200 mg tolmetin), 22.8% microcrystalline cellulose (Avicel PH-102), 14.3% spray-dried lactose (Flowlac 100), 5.0% croscarmellose sodium, and 0.8% magnesium stearate—yielding a total core mass of 350 mg. Granulation is performed in a Collette Gral 10 high-shear mixer with the impeller at 200 rpm and chopper at 1500 rpm; purified water is sprayed at 8.5% w/w of the dry blend mass until a power consumption inflection to 7.8 kW is recorded on the main drive. Over-wetting beyond 9.2% water creates a torque plateau that produces dense agglomerates with a d50 above 300 µm and a consequent weight variation in the tablet press exceeding 3.0% RSD at die table speeds above 80 rpm. The wet mass is passed through a 2.0 mm screen, dried in a Glatt GPCG 3 fluid-bed dryer at an inlet air temperature of 50°C to a final moisture content of 1.2–1.8% as determined by loss-on-drying at 85°C, and dry-milled through a 1.0 mm screen. Lubrication is carried out in a bin blender for 3 minutes at 15 rpm. Tableting on a Fette 2090i rotary press (24 stations, B-tooling) targets a main compression force of 8–12 kN, producing cores of 70–90 N breaking force (tested per ASTM D6175-03) and friability below 0.3% after 100 rotations (USP <1216>). Disintegration time remains within 5–10 minutes in 0.1N HCl at 37°C in compliance with USP <701>. Terminal product: uncoated tolmetin sodium tablet, 200 mg.
If gastric mucosal protection against NSAID-induced irritation is desired, a PVA-based non-enteric film coat is applied to a target weight gain of 3.0%Immediate-release tolmetin sodium tablets are coated with a polyvinyl alcohol (PVA)-based film coating system (Opadry II 85F) to provide taste masking, light protection, and a physical barrier that reduces esophageal adhesion time—an ancillary benefit in patients with reflux sensitivity. The coating suspension is prepared at 15% w/w solids in purified water and must be continuously agitated at 200 rpm with a marine propeller to prevent sedimentation of titanium dioxide and talc platelets. Application is performed in a fully perforated O’Hara Labcoat 60″ coating pan with a gun-to-bed distance of 25 cm and an inlet air temperature of 60°C that maintains a bed temperature of 38–42°C. Spray rate is ramped from 12 g/min/gun to 18 g/min/gun while retaining a pan speed of 4–6 rpm and atomization air pressure at 2.0 bar. The process targets a 3.0% w/w weight gain, corresponding to approximately 12 mg of dry coating per 400 mg tablet core. The coated tablets are then cured in-pan at 40°C for 5 minutes with continuous jog rotation and discharged when exhaust humidity returns to baseline. Coating uniformity and adhesion are verified by scanning electron microscopy on a random sample and by a 30-minute disintegration challenge in 0.1N HCl—the film must rupture within 180 seconds. Regulatory compliance for the coating materials falls under FDA 21 CFR 175.300 (indirect food additives), Ph. Eur. 3.2.2.2 for film coatings, and USP <1662> for water activity control. Terminal product: film-coated tolmetin sodium tablets, 400 mg.
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The compound 1-Methyl-5-(p-toluoyl)-2-pyrroleacetic acid (CAS 26171-23-3, molecular formula C15H15NO3, monoisotopic mass 257.1052) is supplied as a white to off-white crystalline powder with a melting point of 156–158 °C (decomposition) determined by DSC at 10 K/min under nitrogen. Commercially available as a Pharmacopoeial Reference Standard (current lot assay 99.8% by mass balance) and as a certified impurity marker (Tolmetin Related Compound B per USP nomenclature), the free acid serves dual roles in pharmaceutical quality control: calibrator for dissolution profiling and system suitability marker in HPLC impurity methods. Suppliers provide product under catalogue numbers such as USP 1667408 (Tolmetin Related Compound B) and EP T0670000 (Tolmetin for system suitability CRS). The material is prepared by recrystallization from toluene/hexane and dried to constant weight over phosphorus pentoxide at 40 °C under ≤5 mbar vacuum to achieve the anhydrous form.
Long-term stability studies conducted in accordance with ICH Q1A(R2) demonstrate that the free acid remains within specification when stored double-sealed in amber HDPE containers with a silica gel desiccant at 2–8 °C. Under accelerated conditions (40 °C/75% RH), water uptake reaches 1.3% w/w after 14 days, forming a monohydrate pseudopolymorph identifiable by an endothermic peak at 72 °C in DSC and a shift in the carbonyl IR stretch from 1672 cm⁻¹ to 1654 cm⁻¹. Therefore, quantitative vials opened in environments exceeding 60% RH must be re-dried at 60 °C under vacuum (≤5 mbar) for 4 h. The substance is incompatible with strong bases, which cause hydrolytic opening of the pyrrole ring, and with strong oxidizing agents, producing an N-oxide degradant (m/z 274.1). No exotherm is observed in compatibility screening with common tablet excipients (lactose monohydrate, microcrystalline cellulose, magnesium stearate) at a drug load of 10% when tested by differential scanning calorimetry at 5 °C/min from 30 to 300 °C.
For the determination of related substances, compendial methods (USP Tolmetin Sodium Monograph, Ph. Eur. 1760) employ an octadecylsilane chemically bonded silica column (L1 packing, 250 mm × 4.6 mm, 5 µm). The mobile phase consists of acetonitrile and 0.05 M phosphate buffer adjusted to pH 3.0 (45:55 v/v), with UV detection at 313 nm. The free acid elutes at approximately 9.2 min under a flow rate of 1.0 mL/min. The following system suitability parameters derived from six replicate injections of a standard solution at the 0.5 mg/mL level must be met prior to batch release:
| Parameter | Acceptance Criterion | Test Standard |
|---|---|---|
| Resolution (Tolmetin peak / 3-isomer peak) | ≥2.0 | USP <621> |
| Tailing factor (Tolmetin peak, 10% peak height) | ≤2.0 | USP <621> |
| Relative standard deviation (repeatability) | ≤2.0% (n=6) | ICH Q2(R1) |
| Signal-to-noise ratio for 0.05% impurity | ≥10 | Ph. Eur. 2.2.46 |
| Column efficiency (Tolmetin peak) | ≥5000 plates | USP <621> |
The primary process impurity, 1-methyl-4-(p-toluoyl)-2-pyrroleacetic acid (the 3-positional isomer), exhibits a relative retention time of 1.22 ± 0.03. Its limit of quantitation, validated using the standard addition approach in a placebo capsule matrix, is 0.05 µg/mL, corresponding to 0.01% of the nominal drug substance concentration. Quantitation above the 0.15% specification threshold triggers a full investigation under 21 CFR 211.192. An additional late-eluting dimer impurity, formed via intermolecular ester condensation at elevated temperatures during synthesis, is monitored with a relative retention of 2.85 and a reporting threshold of 0.05%.
While all three are acetic acid-derivatized heteroaryl NSAIDs, the pyrrole ring methylation and p-toluoyl substitution pattern impart distinct solubilisation profiles. Saturation shake‑flask measurements in FaSSIF (fasted‑state simulated intestinal fluid, pH 6.5) yield solubility values of 1.8 mg/mL for tolmetin free acid, 4.5 mg/mL for ketorolac tromethamine, and 0.08 mg/mL for indomethacin. In FeSSIF (fed state, pH 5.0), the corresponding figures are 2.9 mg/mL, 5.1 mg/mL, and 0.3 mg/mL. The pKa of the carboxylic acid group, determined potentiometrically in 0.15 M KCl at 25 °C, is 3.5 for tolmetin, compared to 3.5 for ketorolac and 4.5 for indomethacin. Consequently, tolmetin free acid remains predominantly unionized in gastric fluid (pH 1.2, solubility 0.04 mg/mL), requiring salt formation or micronisation to achieve dissolution rates compatible with immediate‑release solid dosage forms. The sodium salt dihydrate, regulated under USP Tolmetin Sodium RS, exhibits a gastric solubility of 12 mg/mL and is therefore the approved active ingredient in commercial capsules (400 mg base equivalent).
The commercially relevant synthesis of 1-Methyl-5-(p-toluoyl)-2-pyrroleacetic acid involves Friedel‑Crafts acylation of 1-methyl-2-pyrroleacetic acid with p-toluoyl chloride in the presence of a Lewis acid catalyst, typically anhydrous aluminium chloride (1.5 equivalents) in dichloromethane at 0–5 °C. The electrophilic substitution on the pyrrole ring is directed by the electron‑donating N‑methyl group associated with the 2‑position, but the 3‑position (meta to the acetic acid side chain) remains susceptible to acylation. Under kinetic control (AlCl₃ pre‑complexed with the acid chloride added dropwise over 60 min), the 5‑acyl isomer (desired product) is formed with a selectivity of approximately 92:8 over the 3-positional isomer. If the reaction mixture is allowed to warm to 25 °C prematurely, thermodynamic equilibration increases the 3‑isomer content to 15–18%, necessitating downstream purification by fractional crystallization from toluene. The recrystallization mother liquor enrichment in the 3‑isomer is monitored by HPLC; a typical batch shows an initial crude assay of 88% (target isomer) with 9% 3‑isomer, and after two recrystallizations, the purity improves to 99.6% with residual isomer of 0.12%. This process sensitivity translates directly into the product specification for the reference standard, where the 3‑isomer limit is set at ≤0.3%. Published data for isomer separation on chiral stationary phases is limited, but an isocratic method using a Chiralpak AD-H column (4.6 × 250 mm, 5 μm) with hexane:ethanol:trifluoroacetic acid (90:10:0.1) achieves baseline resolution (Rs >3.0) of the two regioisomers.
Under ICH Q1B conditions—exposure to visible light of not less than 1.2 million lux hours and ultraviolet energy of not less than 200 W·h/m²—the solid free acid generates two photoproducts detectable by LC‑MS. The major photodegradant (m/z 240.1 [M+H]+) corresponds to decarboxylated 1-methyl-5-(p-toluoyl)pyrrole, forming at a level of 0.28% under UV‑A radiation. The minor species (m/z 274.1) is attributed to a benzophenone‑derived oxidation product. The photodegradation kinetics follow a zero‑order rate of 0.012% h⁻¹ under UV‑A at 25 °C. In solution (methanol, 0.2 mg/mL), the decarboxylation rate accelerates to 0.23% h⁻¹. Consequently, all analytical stock solutions must be protected from ambient laboratory lighting by using low‑actinic volumetric glassware and stored for no longer than 48 hours at 2–8 °C. These data underpin the photoprotection requirements detailed in the certificate of analysis, where the specification for the decarboxy impurity is tightened to ≤0.10% for lots intended as reference standards.
Although the commercial dosage form contains tolmetin sodium dihydrate, the free acid calibrator is specified for the quantitative dissolution analysis outlined in USP Tolmetin Sodium Capsules Monograph. Dissolution is conducted in 900 mL of pH 7.4 phosphate buffer at 37 ± 0.5 °C using USP Apparatus 2 (paddles) at 50 rpm. Free acid calibrator solutions, prepared at 0.44 mg/mL (equivalent to 0.40 mg/mL of the sodium salt), are read against the test solutions at the absorbance maximum of 313 nm. Filter interference is evaluated with three filter types: Whatman GF/D (glass fiber), Millipore PVDF 0.45 µm, and PTFE 0.45 µm. Adsorption loss is ≤1.2% for the PVDF filter when the first 2 mL of filtrate is discarded, satisfying the ≤2% criterion of USP <1092>. The method exhibits linearity across the range 0.044–0.88 mg/mL (r² 0.9998), with a limit of quantitation of 0.02 mg/mL. Pooled intermediate precision data across three laboratories yield an overall RSD of 1.8%. A key difference from using sodium salt calibrators emerges in the dissolution of capsules under acidic conditions (pH 1.2 dissolution medium), where the low intrinsic solubility of the free acid leads to incomplete recovery (61–73% at 30 min) compared to >85% for the sodium salt. This offset is corrected via a molar equivalency factor of 1.120 and a back‑calculation against the label claim, but regulatory filings must explicitly justify the choice of the free acid as the reference standard in lieu of the salt to avoid bioequivalence assumption discrepancies.
| Property | Tolmetin free acid | Tolmetin sodium dihydrate | Ketorolac free acid |
|---|---|---|---|
| CAS | 26171-23-3 | 64490-92-2 | 74103-06-3 |
| Melting point (°C, DSC onset) | 156–158 (dec.) | 243–247 (dec.) | 216–218 |
| Aqueous solubility (pH 1.2, 37 °C) | 0.04 mg/mL | 12 mg/mL | 0.31 mg/mL |
| logP (octanol/water) | 2.6 | 2.3 | 1.8 |
| Retention time (RP‑HPLC, L1, pH 3.0) | 9.2 min | 8.9 min | 11.4 min |
| Photoproduct (RRT) | 0.65 (decarboxy) | 0.65 | 0.72 (ketorolac lactone) |
| COX‑1 IC50 (µM) | 0.3 | — | 0.001 |
In vitro whole‑blood cyclooxygenase inhibition assays provide comparative IC50 values that differentiate the pharmacodynamic footprint. Tolmetin inhibits COX‑1 with an IC50 of 0.3 µM and COX‑2 with 1.1 µM, yielding a COX‑1/COX‑2 ratio of 0.27, indicative of balanced non‑selective inhibition. By contrast, ketorolac tromethamine shows IC50 values of 0.001 µM (COX‑1) and 0.02 µM (COX‑2), revealing a significantly higher potency but similar selectivity ratio. Indomethacin is slightly more COX‑1‑selective with a ratio of 0.015. This subtle biochemical distinction explains why tolmetin’s free acid is often chosen as a calibrator in in‑house bioanalytical method validation for therapeutic drug monitoring, where a cross‑reactivity matrix against structurally related NSAIDs must be established using LC‑MS/MS multiple reaction monitoring transitions (258.1→119.1 for tolmetin, 256.1→105.0 for ketorolac, 358.0→139.0 for indomethacin).
