Monitoring of the degradation kinetics of diatrizoate sodium to its cytotoxic degradant using a stability‐indicating high‐performance liquid chromatographic method

The X‐ray diagnostic agent sodium diatrizoate (DTA) was studied for chemical degradation. The 3,5‐diamino derivative was found to be the alkaline and acidic degradation product. The 3,5‐diamino degradate is also the synthetic precursor of DTA and it is proved to have cytotoxic and mutagenic effects. A sensitive, selective and precise high‐performance liquid chromatographic stability‐indicating method for the determination of DTA in the presence of its acidic degradation product and in pharmaceutical formulation was developed and validated. Owing to the high toxicity of the degradation product, the kinetics of the acidic degradation process was monitored by the developed RP‐HPLC method. The reaction was found to follow pseudo‐first order kinetics. The kinetic parameters such as rate constant (K ) and half‐life (t _½) were calculated under different temperatures and acid concentrations; activation energy was estimated from the Arrhenius plot. The developed RP‐HPLC method depends on isocratic elution of a mobile phase composed of methanol–water (25:75 v /v; pH adjusted with phosphoric acid), and UV detection at 238 nm. The method showed good linearity over a concentration range of 2–100 μg/mL with mean percentage recovery of 100.04 ± 1.07. The selectivity of the proposed method was tested using laboratory‐prepared mixtures. The proposed method has been successfully applied to the analysis of DTA in pharmaceutical dosage forms without interference from other dosage form additives and the results were statistically compared with the official USP method. Validation of the proposed method was performed according to International Conference on Harmonization guidelines.     

Development and validation of a stability‐indicating assay including the isolation and characterization of degradation products of metaxalone by LC‐MS

A stability‐indicating reverse‐phase high‐performance liquid chromatography–mass spectrometric method was developed and validated for the assay of metaxalone through forced degradation under acidic, alkaline, photo, oxidative and peroxide stress conditions. Separation of degradation products was accomplished on a reverse‐phase Phenomenex C₁₈ (250 × 4.6 mm, 5 µm) column thermostated at 25°C using 10 mM aqueous ammonium acetate: methanol (35:65 v/v) as mobile phase in an isocratic mode of elution. The eluents were detected at 275 nm by photo diode array detector and mass detectors connected in series. Two unknown base hydrolysis products of metaxalone were identified and characterized as (a) methyl 3‐(3,5‐dimethylphenoxy)‐2‐hydroxypropylcarbamate and (b) 1‐(3,5‐dimethylphenoxy)‐3‐aminopropan‐2‐ol by MS, ¹H NMR and FTIR spectroscopy. The method was validated as per International Conference on Harmonization guidelines and metaxalone was selectively determined in presence of its degradation impurities, demonstrating its stability‐indicating nature. Copyright © 2013 John Wiley & Sons, Ltd.     

Different stability‐indicating chromatographic methods for specific determination of paracetamol,dantrolene sodium,their toxic impurities and degradation products

A well‐known analgesic (paracetamol, PAR) and skeletal muscle relaxant [dantrolene sodium (DNS)] have been analyzed without interference from their toxic impurities and degradation products. The studied PAR impurities are the genotoxic and nephrotoxic p‐amino phenol (PAP) and the hepatotoxic and nephrotoxic chloroacetanilide, while 5‐(4‐nitrophenyl)‐2‐furaldehyde is reported to be a mutagenic and carcinogenic degradation product of DNS. The five studied components were determined and quantified by TLC–densitometric and RP‐HPLC methods. TLC–densitometry (method 1) used TLC silica gel and chloroform–ethyl acetate–acetic acid–triethylamine (7:3:0.5:0.05, by volume) as the mobile phase with UV scanning at 230 nm, while RP‐HPLC (method 2) was based on separation on a C₁₈ column using methanol–water (55:45, v/v pH 3 with aqueous formic acid) as mobile phase at 1 mL/min and detection at 230 nm. The developed methods were used for determination and quantification of the five studied components in different laboratory‐prepared mixtures. The were also applied for analysis of Dantrelax^® compound capsules where no interference among the studied components with each other or from excipients was observed. The methods were validated as per International Conference on Harmonization guidelines, and they compared favorably with the reported ones.     

Development and validation of a stability‐indicating HPLC method for topiramate using a mixed‐mode column and charged aerosol detector

The analysis of topiramate in the presence of its main degradation products is challenging due to the absence of chromophore moieties and their wide range of polarity. Mixed‐mode chromatography has been used in such cases because it combines two or more modes of separation. Charged aerosol detector is also an alternative since its detection is independent of optical properties and analyte ionization. This study is aimed to develop and validate two new stability‐indicating methods by high‐performance liquid chromatography for the main degradation products of topiramate using mixed‐mode chromatography and a charged aerosol detector. Method 1 employed an Acclaim Trinity P1® column (3.0 mm × 150 mm, 2.7 μm) with a mobile phase comprising of 80% ammonium acetate buffer (20 mM, pH 4.0) and 20% methanol at a flow rate of 0.5 mL/min at 35°C. Method 2 utilized a C18 Acclaim 120® column (4.6 mm × 250 mm; 5 μm) with ACN/water (50:50) at a flow rate of 0.6 mL/min at 50°C. Validation of the two methods demonstrated excellent performance with respect to linearity, precision, accuracy, and selectivity. The limits of detection for topiramate, fructose, sulfate, sulfamate, and compound A were 2.97, 12.08, 4.02, 13.91, and 3.94 μg/mL, respectively.     

Simultaneous determination of aliskiren and hydrochlorothiazide from their pharmaceutical preparations using a validated stability‐indicating MEKC method

A stability‐indicating MEKC method was developed and validated for the simultaneous determination of aliskiren (ALI) and hydrochlorothiazide (HCTZ) in pharmaceutical formulations using ranitidine as an internal standard (IS). Optimal conditions for the separation of ALI, HCTZ and its major impurity chlorothiazide (CTZ), IS and degradation products were investigated. The method employed 47 mM Tris buffer and 47 mM anionic detergent SDS solution at pH 10.2 as the background electrolyte. MEKC method was performed on a fused‐silica capillary (40 cm) at 28°C. Applied voltage was 26 kV (positive polarity) and photodiode array (PDA) detector was set at 217 nm. The method was validated in accordance with the ICH requirements. The method was linear over the concentration range of 5–100 and 60–1200 μg/mL for HCTZ and ALI, respectively (r²>0.9997). The stability‐indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using the PDA detection. Precision and accuracy evaluated by RSD were lower than 2%. The method proved to be robust by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of ALI and HCTZ both individually and in a combined dosage tablet formulation to support the quality control.     

Identification and characterization of forced degradation products and stability‐indicating assay for notoginsenosidefc by using UHPLC‐Q‐TOF‐MS and UHPLC‐MS/MS: Insights into stability profile and degradation pathways

Notoginsenoside Fc, a protopanaxadiol‐type saponin, shows multi‐pharmacological activities. Chemical stability evaluation plays a crucial role in drug development. In this study, the forced degradation behavior of Notoginsenoside Fc was investigated under hydrolytic and oxidative conditions. A specific ultra high performance liquid chromatography with quadrupole time‐of‐flight mass spectrometry was developed for the separation, identification, and characterization of the degradation products of Notoginsenoside Fc. Fifty potential degradation products were formed via deglycosylation, dehydration, hydration, isomerization, side‐chain cleaving, oxidation, and superoxidation. Notoginsenoside Fc was subjected to different pH solutions, temperatures, and time periods to assess its stability. A sensitive ultra high performance liquid chromatography‐tandem mass spectrometry was developed for the quantification of Notoginsenoside Fc, notoginsenoside ST‐4, notoginsenoside Ft1, and relative quantification of notoginsenoside Ft2, 20(R)‐notoginsenoside Ft2, notoginsenoside SFt3, and notoginsenoside SFt4. The assay was linear over the concentration range (R² > 0.997) with the lowest limit of quantification of 0.02 μg/mL for Notoginsenoside Fc, Notoginsenoside ST‐4, and Notoginsenoside Ft1. The intra‐day precision, inter‐day precision, and accuracy of the three analytes were within accepted levels. The degradation kinetics of Notoginsenoside Fc in pH 1 and 3 solutions fits to first‐ and second‐order kinetics, respectively. The degradation of Notoginsenoside Fc is pH‐, temperature‐, and time‐dependent.     

Determination of lumiracoxib by a validated stability‐indicating MEKC method and identification of its degradation products by LC‐ESI‐MS studies

A stability‐indicating MEKC method was developed and validated for the analysis of lumiracoxib (LMC) in pharmaceutical formulations using nimesulide as the internal standard (IS). Optimal conditions for the separation of LMC and degradation products were investigated. The method employed 50 mM borate buffer and 50 mM anionic detergent SDS solution at pH 9.0. MEKC method was performed on a fused‐silica capillary (50 μm id; effective length, 40 cm) maintained at 30°C. The applied voltage was 20 kV and photodiode array (PDA) detector was set at 208 nm. The method was validated in accordance with the International Conference on Harmonisation requirements. The stability‐indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using PDA detection. The degradation products formed under stressed conditions were investigated by LC‐ESI‐MS and the two degraded products were identified. MEKC method was linear over the concentration range of 5–150 μg/mL (r²=0.9999) of LMC. The method was precise, accurate, with LOD and LOQ of 1.34 and 4.48 μg/mL, respectively. The robustness was proved by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of LMC in tablets to support the quality control.     

Development and validation of a RP‐HPLC method for stability‐indicating assay of gemifloxacin mesylate including identification of related substances by LC‐ESI‐MS/MS, 1H and 13C NMR spectroscopy

A validated stability indicating RP‐HPLC assay of gemifloxacin mesylate was developed by separating its related substances on an Inertsil‐ODS3V‐C₁₈ (4.6 × 250 mm; 5 μm) column using 0.1% trifluoroaceticacid (pH 2.5) and methanol as a mobile phase in a gradient elution mode at a flow rate of 1.0 mL/min at 27°C. The column effluents were monitored by a photodiode array detector set at 287 nm. The method was validated in terms of accuracy, precision and linearity as per ICH guidelines. Forced degradation of gemifloxacin (GFX) was carried out under acidic, basic, thermal, photolysis and peroxide conditions and the degradation products were separated and characterized by ESI‐MS/MS, ¹H and ¹³C NMR spectroscopy. The method was successfully applied to the analysis of bulk drugs and the recoveries of gemifloxacin and impurities were in the range of 97.60–102.90 and 96.99–102.10%, respectively. No previous reports were found in the literature on identification of degradation products of gemifloxacin. Copyright © 2011 John Wiley & Sons, Ltd.     

Comprehensive stability‐indicating high‐performance liquid chromatography coupled with diode array detection method for simultaneous determination of amprolium hydrochloride and ethopabate in powder dosage form for veterinary use

This research deals with the development of a stability‐indicating high‐performance liquid chromatography method for simultaneous determination of amprolium hydrochloride and ethopabate. To the best of our knowledge, no comprehensive stability‐indicating method has been reported for analysis of this mixture. Separation was achieved using Kromasil cyano column with gradient elution of the mobile phase composed of sodium hexane sulfonate solution and methanol. Quantification was based on measuring peak areas at 266 nm. Amprolium and ethopabate peaks eluted at retention times 10.42 and 18.53 min, respectively. The proposed procedure was validated with respect to system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits. Linearity ranges for amprolium and ethopabate were 1.5–240 and 1–160 μg/mL, respectively. Analytes were subjected to stress conditions of hydrolysis, oxidation and thermal degradation. The proposed method enabled resolution of drugs from their forced‐degradation products and amprolium related substance (2‐picoline). Moreover, specificity was verified by resolution of the analytes from about 22 drugs used in antimicrobial veterinary products. The validated method was successfully applied to assay of the combined veterinary powder dosage form, additionally it was implemented in the accelerated stability study of the dosage form when stored for six months at 40°C and 75% relative humidity.     

Stability‐indicating chromatographic and chemometric methods for environmentally benign determination of canagliflozin and its major degradation product; A comparative study and greenness assessment

Recently, concepts of sustainable developments, like considering the environmental effect of chemicals used and the amount of hazardous wastes produced, has gained much interest. In this work, a recently approved treatment for type II diabetes mellitus, canagliflozin, was quantified along with its degradation product by two eco‐friendly methods. The first was a specific green HPLC method using a C₁₈ column as a stationary phase and a mobile phase consisting of methanol–water (98:2, v/v) pumped at a flow rate of 1 mL/min with UV detection at 225 nm, and using ibuprofen as an internal standard. The second method was a partial least square chemometric method with the wavelength range 220–320 nm and the data was autoscaled as a preprocessing step for determination of canagliflozin and its degradation product. The greenness profile of the developed methods was studied and compared with the reported methods. The proposed methods were suitable alternatives for the environmentally harmful reported methods for quality control analyses of canagliflozin‐containing samples, analysis of pharmaceutical formulations and sensitive tracing of its possible degradation product. The methods were validated as per International Conference on Harmonization guidelines and statistically compared with the reported HPLC method.     

Optimization of a validated stability‐indicating RP‐LC method for the determination of fulvestrant from polymeric based nanoparticle systems,drugs and biological samples

Fulvestrant is used for the treatment of hormone receptor‐positive metastatic breast cancer in postmenopausal women with disease progression following anti‐estrogen therapy. Several reversed‐phase columns with variable silica materials, diameters, lengths, etc., were tested for the optimization study. A good chromatographic separation was achieved using a Waters X‐Terra RP₁₈ column (250 × 4.6 mm i.d. × 5 µm) and a mobile phase, consisting of a mixture of acetonitrile–water (65:35; v/v) containing phosphoric acid (0.1%). The separation was carried out 40°C with detection at 215 nm.The calibration curves were linear over the concentration range between 1.0–300 and 1.0–200 µg/mL for standard solutions and biological media, respectively. The proposed method is accurate and reproducible. Forced degradation studies were also realized. This fully validated method allows the direct determination of fulvestrant in dosage form and biological samples. The average recovery of the added fulvestrant amount in the samples was between 98.22 and104.03%. The proposed method was also applied for the determination of fulvestrant from the polymeric‐based nanoparticle systems. No interference from using polymers and other excipients was observed in in vitro drug release studies. Therefore an incorporation efficiency of fulvestrant‐loaded nanoparticle could be determined accurately and specifically. Copyright © 2014 John Wiley & Sons, Ltd.     

Characterization of forced degradation products of pazopanib hydrochloride by UHPLC‐Q‐TOF/MS and in silico toxicity prediction

Pazopanib (PZ), an anti‐cancer drug, was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress conditions as per International Conference on Harmonization guidelines. A selective stability indicating validated method was developed using a Waters Acquity UPLC HSS T3 (100 × 2.1 mm, 1.7 µm) column in gradient mode with ammonium acetate buffer (10 m m , pH 5.0) and acetonitrile. PZ was found to degrade only in photolytic conditions to produce six transformation products (TPs). All the TPs were identified and characterized by liquid chromatography/atmospheric pressure chemical ionization–quadrupole‐time of flight mass spectrometry experiments in combination with accurate mass measurements. Plausible mechanisms have been proposed for the formation of TPs. In silico toxicity was predicted using TOPKAT and DEREK softwares for all the TPs. The TP, N4‐(2,3‐dimethyl‐2H‐indazol‐6‐yl)‐N4‐methylpyrimidine‐2,4‐diamine, was found to be genotoxic, whereas all other TPs with sulfonamide moiety were hepatotoxic. The data reported here are expected to be of significance as this study foresees the formation of one potential genotoxic and five hepatotoxic degradation/transformation products. Copyright © 2015 John Wiley & Sons, Ltd.     

PLA‐based nanoparticles with tunable hydrophobicity and degradation kinetics

In this work, the preparation of poly(lactic acid) (PLA)‐based degradable nanoparticles (NPs) with tunable hydrophobicity and degradation kinetics via starved emulsion free‐radical polymerization is studied. The synthesis of macromonomers, constituted of a tunable number of lactic acid units functionalized with 2‐hydroxyethyl methacrylate (HEMA), has been performed via bulk ring opening polymerization (ROP) of L, L‐ lactide catalyzed with 2‐ethylhexanoic acid tin (II) salt. Macromonomers were characterized through SEC, NMR, and FTIR and are subsequently polymerized through monomer‐starved semi‐batch emulsion polymerization (MSSEP). The effect on the polymerization process of various emulsifiers on the final diameter and particle size distribution has been studied. The resulting PLA‐based NPs are characterized by a narrow size distribution and a small particle size, down to 25 nm. Finally, a degradation study of selected NPs has been carried out to verify their degradability in aqueous media. It has been demonstrated the complete degradability of these PLA‐based NPs which occurs upon the hydrolysis of the PLA pendant chains leaving poly‐HEMA chains, which, being hydrophilic causes the NPs to dissolve in the aqueous suspension. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Stability‐indicating HPLC assay for lysine–proline–valine (KPV) in aqueous solutions and skin homogenates

A simple, sensitive and stability‐indicating high‐performance liquid chromatographic (HPLC) assay method was developed and validated for a bioactive peptide, lysine–proline–valine (KPV) in aqueous solutions and skin homogenates. Chromatographic separation was achieved on a reversed phase Phenomenex C₁₈ column (4.6 × 250 mm, packed with 5 µm silica particles) with a gradient mobile phase consisting of 0.1% trifluoroacetic acid (TFA) in water (A) and 0.1% TFA in acetonitrile (B). The proposed HPLC method was validated with respect to accuracy, precision, linearity, repeatability, limit of detection (LOD) and limit of quantitation (LOQ). The calibration curve was linear with a correlation coefficient (r) of 0.9999. Relative standard deviation values of accuracy and precision experiments were <2. The LOD and LOQ of KPV were 0.01 and 0.25 µg/mL, respectively. Under stress conditions (acid, alkali and hydrogen peroxide) KPV yielded lys–pro–diketopiperazine as major degradation product, which was identified by flow injection MS analysis. The developed HPLC method was found to be efficient in separating the active peptide from its degradation products generated under various stress conditions. Also, the validated method was able to separate KPV from other peaks arising from endogenous components of the skin homogenate. Copyright © 2014 John Wiley & Sons, Ltd.     

Stability and degradation products of imipenem applying high‐resolution mass spectrometry: An analytical study focused on solutions for infusion

Carbapenems show recognized instability in aqueous solutions; therefore some care must be taken in their handling and preparation and their use in the hospital environment. The stability and degradation products of imipenem were investigated from conditions that simulate its clinical use. For this, a simple stability‐indicating method by HPLC‐DAD was validated with a focus on the quantitation of drug concentration remaining from infusion solutions (sodium chloride 0.9% and glucose 5%). The degradation products formed were identified by high‐resolution mass spectrometry (ESI‐Q‐TOF‐MS/MS), with detection of the [M + H]⁺ ions at m/z 318 (DP‐1), m/z 599 (DP‐2) and m/z 658 (DP‐3). The most probable elemental compositions were obtained with a high degree of confidence, where the error between the masses observed and calculated was 1.25 ppm for DP‐1, ?0.33 ppm for DP‐2 and 1.82 ppm for DP‐3. The DP‐1 degradation product resulted from cleavage of the β‐lactam ring; DP‐2 corresponded to the drug dimer; and DP‐3 was generated from the interaction between imipenem and cilastatin. The proposed method provides a safe and reliable alternative for the quantitation of imipenem, and the stability data obtained by ESI‐Q‐TOF help in understanding the drug behavior under the conditions of clinical use.     

Reagent‐free and pH‐independent degradation of N‐nitrosamines using electrons generated via corona discharge at ambient pressure

Traditional degradation methods for N‐nitrosamines are either confined with acid solution or required for additional chemical reagents to guarantee high reaction efficiency. Herein, we demonstrate a facile and effective way for reagent‐free and pH‐independent degradation of N‐nitrosamines, which was induced by free electrons generated via corona discharge at ambient pressure. The highly reactive free electron is produced in situ and responsible for degradation of three N‐nitrosamines, which was also theoretically confirmed. N‐nitrosamines were believed to be reduced by electrons and to form the radical anion, which underwent a selectively heterolytic cleavage of the N–NO bonds to form the corresponding secondary amines as the degradation products.     

Stability‐indicating chromatographic methods for determination of flecainide acetate in the presence of its degradation products; isolation and identification of two of its impurities

In this work, two stability‐indicating chromatographic methods have been developed and validated for determination of flecainide acetate (an antiarrhythmic drug) in the presence of its degradation products (flecainide impurities; B and D). Flecainide acetate was subjected to a stress stability study including acid, alkali, oxidative, photolytic and thermal degradation. The suggested chromatographic methods included the use of thin layer chromatography (TLC‐densitometry) and high‐performance liquid chromatography (HPLC). The TLC method employed aluminum TLC plates precoated with silica gel G.F₂₅₄ as the stationary phase and methanol–ethyl acetate–33% ammonia (3:7:0.3, by volume) as the mobile phase. The chromatograms were scanned at 290 nm and visualized in daylight by the aid of iodine vapor. The developed HPLC method used a RP‐C₁₈ column with isocratic elution. Separation was achieved using a mobile phase composed of phosphate buffer pH 3.3–acetonitrile–triethylamine (53:47:0.03, by volume) at a flow rate of 1.0 mL/min and UV detection at 292 nm. Factors affecting the efficiency of HPLC method have been studied carefully to reach the optimum conditions for separation. The developed methods were validated according to the International Conference on Harmonization guidelines and were applied for bulk powder and dosage form. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis and hydrolytic degradation of a random copolymer derived from 1,4‐dioxan‐2‐one and glycolide

Novel biodegradable copolymers, poly(1,4‐dioxan‐2‐one‐co‐glycolide) [P(DON‐co‐GA)] containing a high proportion of 1,4‐dioxan‐2‐one (DON), were synthesized by copolymerizations of DON and glycolide (GA) at 120 °C for 16 h using stannous octoate as catalyst. Chemical composition and microstructural variation of the resulting copolymer were investigated by ¹H‐ and ¹³C NMR and thermal properties by differential scanning calorimetry (DSC). From the ¹³C NMR spectra, it was observed that, apart from the expected preponderance of DON sequences, the minor component, GA, was indeed distributed at various points along the copolymer chain rather than incorporated as distinct blocks, which is consistent with a random sequence distribution. This view also was supported by the DSC results, which showed that most copolymers were amorphous except for one with a relatively high fraction of DON. The conclusion that it was a random structure rather than a statistical copolymer is discussed, using the theories about the mechanism of this type of polymerization in current as a reference. P(DON‐co‐GA) films were prepared by casting the copolymer solution in hexafluoroisopropanol (HFIP) with two concentrations of the polymeric solution (10 and 25 wt %). The in vitro hydrolytic degradation behaviors of these films were studied in phosphate buffer solution (pH = 7.4) at 37 °C and characterized by DSC, scanning electron microscopy, weight loss, and change in inherent viscosity. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 2558–2566, 2004     

Hydrogels for colon‐specific drug delivery: Swelling kinetics and mechanism of degradation in vitro

Hydrogels based on n‐alkyl methacrylate esters (n‐AMA) of various chain lengths, acrylic acid, and acrylamide crosslinked with 4,4′‐di(methacryloylmino)azobenzene were prepared. Swelling kinetics and the mechanism of degradation in vitro of the hydrogels as well as the mutual relations between both were studied by the immersion of slabs in buffered solutions at pH 7.4. The diffusion of water into the slabs was discussed on the stress‐relaxation model of polymer chains. The results obtained agreed well with Schott's second‐order diffusion kinetics. The gels are degradable by anaerobes in the colon. The results obtained showed that the degradation of networks proceeded via a pore mechanism. The factors influencing the swelling and degradation of the gels include the degree of crosslinking, the lengths of the n‐AMA side chains, and the composition. These hydrogels have the potential for colon‐specific drug delivery. © 2001 John Wiley & Sons, Inc. J Polym Sci Part B: Polym Phys 39: 3128–3137, 2001     

An investigation of the thermal and thermo‐oxidative degradation of polybenzoxazines with a reactive functional group

The thermal behavior of a series of polybenzoxazines based on 3‐aminophenylacetylene has been investigated. The effect of reactive amine on the thermal cleavage of the Mannich base is examined under both inert and oxidative environments. It has been shown that the thermal stability of polybenzoxazines is substantially improved by the reactive amine. Various biphenols are found to have insignificant effect on the thermal stability of this series of polybenzoxazines. These nitrogen containing phenolic resins are nonflammable polymers. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 647–659, 1999