Product Information：
Product Number: A017081
English Name: Apremilast Impurity 81
English Alias: N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-((2-hydroxyethyl)sulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide
CAS Number: 2487573-01-1
Molecular Formula: C₂₃H₂₆N₂O₈S
Molecular Weight: 490.53
Advantages：
High purity and structural confirmation：HPLC purity ≥99.0%, with structure verified by 1H NMR, 13C NMR, HRMS, and IR spectroscopy, meeting strict requirements of FDA and EMA for impurity reference standards, enabling precise qualitative and quantitative analysis.
Controllable stability：Stable for 24 months when stored at -20°C in the dark, with a degradation rate <1% after 7 days at room temperature in solution (e.g., acetonitrile-water system), suitable for long-term quality monitoring and stability studies.
Strong process specificity：As a characteristic impurity from sulfonylation or amidation side reactions in apremilast synthesis, it accurately tracks process risks of excessive ethylation reagent or out-of-control hydroxy sulfonylation reactions.
Applications：
Pharmaceutical impurity detection：Used for LC-MS/MS detection of Impurity 81 in apremilast APIs and formulations, controlling its content ≤0.1% in accordance with ICH Q3A standards to ensure compliance with quality requirements for PDE4 inhibitor drugs.
Synthesis process optimization：In sulfonylation or amidation reactions, monitoring impurity content (e.g., adjusting sulfonylating reagent dosage or reaction pH to reduce impurity from 1.2% to 0.1%) optimizes reaction conditions to minimize by-product formation.
Analytical method development：Serves as a sulfonyl-containing impurity reference standard for establishing specific detection methods, such as ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), achieving accurate quantification using characteristic sulfonyl fragment ions (m/z 491.1→329.0) (detection limit LOD=0.01ng/mL).
Toxicological research support：Provides samples for evaluating the potential toxicity of sulfonyl impurities, facilitating in vitro cytotoxicity tests and in vivo pharmacokinetic studies to meet regulatory requirements for impurity safety assessment.
Background Description：
Apremilast is an oral PDE4 inhibitor used for treating psoriatic arthritis and plaque psoriasis. During its synthesis, Impurity 81 may be generated if sulfonylation reactions (e.g., of 2-hydroxyethyl sulfonyl chloride with amino groups) or amidation reactions are not properly controlled. The impurity’s sulfonyl and ester groups may affect drug metabolic stability and target binding ability. According to the ICH M7(R1) guideline, strict limit control of such process-related impurities is required.
Research Status：
Advances in detection technology：UPLC-MS/MS is employed using a C18 column (1.7μm, 2.1×100mm) with 0.1% formic acid aqueous solution-acetonitrile (gradient elution) as the mobile phase, combined with multiple reaction monitoring (MRM) mode, achieving a limit of quantitation (LOQ) as low as 0.05ng/mL for precise trace impurity detection.
Formation mechanism research：This impurity mainly originates from excessive addition of 2-hydroxyethyl sulfonyl chloride in sulfonylation reactions or residues of acetic anhydride in amidation reactions. Reacting at low temperature (0℃) and using catalytic amounts of triethylamine can reduce impurity formation by over 90%.
Safety evaluation：In vitro Ames tests showed no mutagenicity at concentrations ≤100μg/dish, but mild hepatic enzyme elevation was observed in high-dose groups (150mg/kg) during canine repeated dosing tests. Based on toxicological data, a recommended limit of ≤0.07% is proposed
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