N-acetyl-L-glutamic Acid
- Название продукта: N-acetyl-L-glutamic Acid
- Сайт Factroy: Округ Юду, Ганьчжоу, Цзянси, Китай
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- N-acetyl-L-glutamic Acid is typically used in formulations when pH and osmolality must be controlled within specific ranges.
| Код ТН ВЭД | 193712 |
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In solid-phase peptide synthesis, N-acetyl-L-glutamic acid is first converted to a γ-tert-butyl-protected derivative before activation of the α-carboxyl group. The α-nitrogen is already acetylated, so the residue functions only as an N-terminal cap and cannot be extended. The protected derivative is coupled to resin-bound peptides with free N-terminal amines on automated synthesizers operating at 0.05–5.0 mmol scale. Activation is performed with HATU and N,N-diisopropylethylamine or with DIC and Oxyma in anhydrous dimethylformamide or N-methyl-2-pyrrolidone at 0–4 °C for 5–10 min. Coupling proceeds at 20–25 °C for 30–60 min in a polypropylene reactor fitted with a sintered PTFE frit. Ninhydrin or 2,4,6-trinitrobenzenesulfonic acid spot tests detect residual free amine. Cleavage using trifluoroacetic acid, triisopropylsilane, and water at 95:2.5:2.5 v/v/v removes side-chain protecting groups and releases the capped peptide. The crude material is precipitated in cold methyl tert-butyl ether and analyzed by reversed-phase HPLC according to USP <621>. Because the acetyl group blocks Edman degradation at the N-terminus, identity confirmation requires electrospray mass spectrometry rather than sequencing alone. The D-enantiomer content of N-acetyl-L-glutamic acid is controlled by chiral HPLC because D-enantiomer contamination produces diastereomeric capped peptides that are difficult to remove by preparative chromatography.
How Does N-Acetyl-L-Glutamate Function as an Allosteric Probe in CPS1 Enzyme Assays?
N-acetyl-L-glutamic acid serves as the physiologically relevant allosteric activator of carbamoyl phosphate synthetase I, not as a substrate. In diagnostic enzyme activity measurements, the compound is added to isolated liver mitochondrial matrix fractions or to recombinant human CPS1 preparations in millimolar concentration ranges established by titration for each matrix. The assay monitors citrulline formation via the diacetyl monoxime colorimetric reaction or by reversed-phase HPLC after pre-column o-phthaldialdehyde derivatisation. Reaction media are maintained at pH 7.2–7.6 and 37 °C with saturating concentrations of ATP, ammonium bicarbonate, magnesium chloride, and N-acetyl-L-glutamic acid. Parallel incubations run with and without the compound distinguish CPS1 activation from the activity of N-acetylglutamate synthase. Lack of stimulation in a sample containing CPS1 protein suggests either enzyme deficiency or an interfering inhibitor in the mitochondrial extract. Published data for this specific diagnostic configuration are limited outside specialized metabolic laboratories. No ISO harmonized standard covers the entire procedure; each laboratory establishes reference intervals using its own sample preparation and detection platform. The assay design therefore treats N-acetyl-L-glutamic acid as a reagent with lot-to-lot variability controlled by the laboratory, not as a certified reference material.
When immobilized L-aminoacylase is used in continuous resolution of N-acetyl-DL-glutamic acid, N-acetyl-L-glutamic acid is employed as the single-enantiomer substrate probe for verification of reactor selectivity. The racemic feedstock is prepared in water and adjusted to pH 7.0–7.5 with sodium hydroxide or ammonia before entering a jacketed glass column packed with microbial L-aminoacylase immobilised on DEAE-Sephadex or an equivalent carrier. The enzyme carries out selective hydrolysis of the L-enantiomer; effluent samples contain L-glutamic acid and unreacted N-acetyl-D-glutamic acid. Pure N-acetyl-L-glutamic acid is injected as a system-suitability challenge before racemic campaigns to confirm that the column retains stereoselectivity under the current feed conditions. Equipment includes peristaltic feed pumps, in-line pH electrodes, conductivity sensors, and column jackets rated for 60 °C operation. Residence time, substrate concentration, and temperature are adjusted according to the immobilization carrier. Published data for this specific configuration are limited to vendor-specific technical bulletins and process development reports. Product fractions are concentrated under reduced pressure at 50–60 °C and crystallised at pH 3.2–3.4. Optical rotation and chiral HPLC are used to confirm enantiomeric excess for the L-glutamic acid product and to monitor residual N-acetyl-L-glutamic acid in the mother liquor.
Reference Standard Method Packages for HILIC-MS Metabolomics Panels
N-acetyl-L-glutamic acid is used as a calibration standard in targeted metabolomics methods that quantify N-acetylated amino acids in human plasma, urine, and hepatocyte culture media. Primary stock solutions are prepared in water or methanol at concentrations bracketing expected biological concentrations. Matrix-matched calibration curves are constructed at 6–8 concentration levels to correct for ion suppression. Chromatographic separation uses a zwitterionic or amide hydrophilic interaction column with 2.1 mm internal diameter and a mobile-phase gradient of acetonitrile and 10 mmol/L ammonium acetate adjusted to pH 4.0. Detection is performed on a triple-quadrupole mass spectrometer in multiple reaction monitoring mode. The transition for N-acetyl-L-glutamic acid is tuned specifically because in-source dissociation may remove water from the terminal carboxyl group. Where available, isotope-labelled internal standards are added before protein precipitation to control extraction variability. The method is validated for linearity, lower limit of quantification, carryover, and intra-run precision according to ICH Q2(R1) or CLSI C62-A. Stock solution stability is established at −20 °C for controlled intervals; published data for this specific configuration are limited, and extrapolation across different HILIC column chemistries is not recommended.
When N-Acetylated Glutamic Acid is Converted to Carboxyl-Activated Intermediates
Because the α-nitrogen is protected by the acetyl group, the α-carboxyl of N-acetyl-L-glutamic acid can be converted to amide or ester derivatives without α-amine interference. The compound is dissolved in anhydrous tetrahydrofuran or dichloromethane and treated with dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in the presence of N-hydroxysuccinimide. The resulting activated ester is reacted at 0–5 °C with the target alcohol or amine. Coupling completion is monitored by thin-layer chromatography using a mobile phase containing chloroform, methanol, and acetic acid to suppress free carboxyl tailing. Selective modification of the γ-carboxyl requires temporary protection of the α-carboxyl; residual unprotected γ-carboxyl can participate in intramolecular anhydride formation under prolonged activation. Strong aqueous alkali above pH 10 or prolonged heating above 80 °C hydrolyzes the acetyl protecting group and liberates L-glutamic acid; this boundary defines the work-up envelope for the downstream synthesis. Purification is performed by recrystallisation from ethyl acetate and hexane or by normal-phase flash chromatography on silica gel 60 Å pore size. Residual solvent content is controlled according to ICH Q3C and USP <467>. Final products are characterised by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance, and high-resolution mass spectrometry.
For cosmetic emulsions and aqueous hair-conditioning systems, N-acetyl-L-glutamic acid is used as a water-soluble amino acid derivative with a skin-conditioning function listed in CosIng. The material is pre-dissolved in the aqueous phase at 20–25 °C before combination with the oil phase. No Annex III restriction applies under Regulation (EC) No 1223/2009. Manufacturing hygiene follows ISO 22716:2007. Finished product preservation is evaluated by challenge testing according to ISO 11930. The pH of the finished emulsion is maintained between 4.5 and 6.0 with lactate or citrate buffers because the carboxyl groups are ionized above neutral pH. Solubility in hydroalcoholic systems decreases at high ethanol concentration; published data for this specific configuration are limited. The raw ingredient is stored in sealed, dry containers at controlled room temperature to avoid moisture uptake. Compatibility testing with cationic conditioning agents is required because the anionic carboxyl groups may interact with quaternary ammonium polymers at high use levels.
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- N-acetyl-L-glutamic Acid Производится в соответствии с системой качества ISO 9001 и отвечает соответствующим нормативным требованиям.
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The product designated as N-acetyl-L-glutamic acid, CAS 1188-37-0, linear formula C7H11NO5, and molecular weight 189.17 g/mol, is supplied as a white to off-white crystalline powder. Supplier-specific model designations include NAG-Pharm-99 and NAG-Tech-98, where the numerical suffix denotes the minimum assay on the anhydrous basis by high-performance liquid chromatography aligned with USP <621>. The acetylated α-amino group of the L-glutamic acid backbone yields a dicarboxylic acid derivative with two free carboxyl groups and no α-amino protonation site, altering aqueous ionization, metal-chelation, and Maillard-reactivity profiles relative to the parent amino acid. The material is handled as a non-sterile active pharmaceutical intermediate and biochemical research reagent; for sterile filtration or parenteral processing, additional bioburden and endotoxin controls are applied.
Typical bulk properties include tapped density between 0.55 g/cm³ and 0.75 g/cm³ for milled lots, and a melting range of 194–197 °C with decomposition measured by differential scanning calorimetry at 10 K/min under nitrogen. Loss on drying at 105 °C for 2 h is controlled to ≤0.5%. The optical rotation [α]D20 is release-tested, with a typical acceptance range of -15.0° to -18.0° at c=1 in water using a 100 mm polarimeter cell. Published data for this specific configuration is limited to supplier certificates of analysis rather than a harmonized pharmacopoeial monograph; the rotation limit is therefore established against a qualified reference standard.
Why Does N-Acetylation Suppress Maillard Reactivity in Hot-Fill Cell Culture Feeds?
Because the α-amino group is acetylated, the molecule cannot form the Schiff-base intermediates required for non-enzymatic browning with reducing sugars. L-Glutamic acid exists as a zwitterion in neutral aqueous solution with a protonated α-amino group and two deprotonated carboxyl groups at pH 7.4; the N-acetyl derivative retains only the α-carboxyl and γ-carboxyl ionisations. The result is a lower isoelectric point, reduced nucleophilic amino reactivity, and stronger reversed-phase retention. Under USP <621> conditions with a C18 column and 0.1% trifluoroacetic acid/acetonitrile gradient, N-acetyl-L-glutamic acid separates from L-glutamic acid with a resolution ≥2.0, the acetylated derivative eluting later due to increased hydrophobic surface area. In hot-fill cell culture feeds containing glucose, the free amino acid produces coloured condensation products measurable as an absorbance increase at 420 nm after 2 h at 121 °C in 0.1 M phosphate buffer at pH 7.4; the N-acetyl derivative remains negative under the same conditions.
Representative release specifications for the pharmaceutical intermediate grade are listed in Table 1. The limits are aligned with ICH Q3A for unspecified impurities and with USP general chapters for compendial test methods where applicable.
| Parameter | Acceptance criterion | Method or standard |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Assay, anhydrous basis | 98.5–101.0% | HPLC, USP <621> |
| Specific optical rotation | -15.0° to -18.0° (c=1, water, 20 °C) | Polarimetry |
| Loss on drying | ≤0.5% (105 °C, 2 h) | USP <731> |
| Residue on ignition | ≤0.1% | USP <281> |
| Chiral impurity, D-isomer | ≤0.5% | Chiral HPLC, area normalisation |
| Any unspecified impurity | ≤0.10% | HPLC, area normalisation |
| Heavy metals | ≤10 ppm | USP <231> |
| Residual solvents | Methanol ≤3000 ppm; dichloromethane ≤600 ppm | USP <467> |
| Endotoxin, if specified for parenteral processing | ≤0.5 EU/mg | USP <85> |
| Microbial limits | Total aerobic count ≤10² CFU/g; yeast/mould ≤10¹ CFU/g | USP <61> |
Under production-scale vacuum drying at 40–50 °C and 10–30 mbar for 6–8 h, residual ethanol is reduced below 5000 ppm without particle fusion. If the nitrogen purge is interrupted during discharge, the fine fraction absorbs moisture above 60% RH, causing the material to bridge in the rotary valve and requiring manual clearing. The product is therefore discharged under a dry nitrogen blanket with a dew point ≤-40 °C. Aqueous solutions are subject to pH-dependent amide hydrolysis; storage of a 5% w/v solution at 2–8 °C under nitrogen for no more than 24 h limits the release of acetic acid and L-glutamic acid to below the limit of unspecified impurities.
Residual Solvent and Elemental Impurity Control for Non-Compendial Active Substances
Residual solvent and elemental impurity profiles are specified according to ICH Q3C and ICH Q3D Option 1. If the final crystallisation is performed from ethanol-water, the ethanol limit is ≤5000 ppm; when dichloromethane is used for recrystallisation, its Class 2 limit of ≤600 ppm under USP <467> applies. Elemental impurities are evaluated by inductively coupled plasma mass spectrometry; for a parenteral drug substance with a daily intake of 10 g, the ICH Q3D Option 1 limits for lead, cadmium, arsenic, and mercury are ≤0.5 ppm, ≤0.2 ppm, ≤1.5 ppm, and ≤0.3 ppm, respectively. Because no harmonized monograph exists for N-acetyl-L-glutamic acid, release and stability specifications are typically established under ICH Q6A for non-compendial active substances, with the assay method validated for specificity, linearity, accuracy, and precision across the range 80–120% of the nominal concentration.
Use of the title compound as a pharmaceutical intermediate is concentrated in the preparation of N-carbamoyl-L-glutamic acid, a structural analogue of the natural carbamoyl phosphate synthetase I activator. A representative two-step sequence involves activation of the γ-carboxyl group via O-acylisourea formation with N,N'-dicyclohexylcarbodiimide in tetrahydrofuran at 0–5 °C, followed by coupling with ammonia or a protected carbamoyl synthon; the α-carboxyl group is retained as the free acid for final crystallisation from 2-propanol/water (85:15). Unreacted N-acetyl-L-glutamic acid is removed by washing with 0.1 M hydrochloric acid, and the final product purity is confirmed at ≥99.5% by HPLC. In cell-free enzyme studies, the L-isomer activates carbamoyl phosphate synthetase I with an apparent activation constant in the low-micromolar range; the D-isomer is inactive under the same assay conditions, making chiral purity a release-critical attribute.
When Free Acid Is Converted to the Monosodium Salt for Lyophilised Formulations
When the free acid is replaced by the monosodium salt in aqueous lyophilisation, the dissolution behaviour and cake morphology change substantially. The free acid requires stoichiometric neutralisation with sodium hydroxide to achieve complete dissolution at concentrations above 5% w/v in water at 20 °C. The resulting monosodium salt has a solution pH between 6.5 and 7.5 and can be lyophilised from 20 mM Tris-HCl at pH 7.4 without collapse if the product temperature is maintained below the glass transition temperature of the frozen matrix. Free acid lyophilisation from unbuffered water yields a partially collapsed cake because the dissolved solid depresses the collapse temperature below -30 °C. The monosodium salt is not isolated as a single crystalline polymorph in most production batches; it is prepared in situ from the free acid and filtered through a 0.2 µm sterilising-grade membrane before freeze-drying. Each gram of free acid neutralised with 1.0 equivalent of sodium hydroxide contributes 122 mg of sodium ion per 189.17 mg of N-acetyl-L-glutamic acid, which must be included in the finished dosage-form sodium calculation.
Unlike free L-glutamic acid, the N-acetylated derivative does not form coloured condensation products with reducing sugars because the acetylated α-amino group cannot participate in Schiff-base formation. This difference is used in incoming-material identification and in the design of hot-sterilised cell culture media. Compared with the D-isomer, only the L-configuration activates carbamoyl phosphate synthetase I; the D-isomer is therefore controlled as a chiral impurity at ≤0.5%. Compared with N-acetyl-L-glutamine, which contains an amide side chain and a free α-amino group, the title compound behaves as a more acidic species and does not liberate ammonia during prolonged aqueous storage. Table 2 summarises relevant differences across structurally related products.
| Property | N-acetyl-L-glutamic acid | L-glutamic acid | N-acetyl-D-glutamic acid | N-acetyl-L-glutamine |
|---|---|---|---|---|
| CAS number | 1188-37-0 | 56-86-0 | 19146-55-5 | 2490-97-3 |
| Molecular weight | 189.17 g/mol | 147.13 g/mol | 189.17 g/mol | 188.18 g/mol |
| Chiral configuration | L | L | D | L |
| Carbamoyl phosphate synthetase I activation | Active | Negligible | Inactive | Not established |
| Maillard reactivity with glucose at 121 °C | Negative | Positive | Negative | Negative |
| Aqueous pH of 1% w/v solution | Approximately 2.5–3.0 | Approximately 3.2 | Approximately 2.5–3.0 | Approximately 5.0–6.0 |
| Typical function in synthetic routes | Protected acidic building block; CPS1 activator intermediate | Cell culture nutrient; neurotransmitter precursor | Chiral reference standard | Stabilised L-glutamine source |
Operational boundaries for the free acid include storage below 25 °C and 60% RH in closed containers under inert gas. Pre-drying at 60 °C under vacuum for 4 h is required when the container has been opened at ambient humidity above 60% RH. Prolonged contact with strong aqueous ammonia at pH above 10 and temperatures above 40 °C leads to deacetylation to L-glutamic acid and should be avoided. The compound is not supplied as a sterile material; use in parenteral processing requires dissolution in Water for Injection, sterilising filtration, and endotoxin verification before final dosage-form assembly.
