Synthesis and characterization of potential impurities of Oxcarbazepine drug substance: An antiepileptic agent

Oxcarbazepine is a drug substance used to treat epilepsy. During its bulk synthesis of various impurities formation will be observed. Herein we describe the formation, synthesis and characterization of four potential impurities, namely, N-acetyl Oxcarbazepine, N-formyl Oxcarbazepine, N-carbamoyl Oxcarbazepine, and Oxcarbazepine dimer. These impurities are listed in several Pharmacopoeias and the control of these impurities below the threshold level is essential. Our study will be a guide for making these reference standards.     

达比加群酯的合成

3-硝基-4-氯苯甲酸(2)经甲胺化得3-硝基-4-甲氨基苯甲酸(3),2-氨基吡啶与丙烯酸乙酯经迈克尔加成得3-[(吡啶-2-基)氨基]丙酸乙酯(5),化合物3与5经缩合、催化氢化得3-{[(3-氨基-4-甲胺基)苯甲酰基](吡啶-2-基)氨基}丙酸乙酯(7),化合物7再与N-(4-氰基苯基)甘氨酸(8)酰化、环合和Pinner反应,最后与氯甲酸正己酯反应得到达比加群酯(1),总收率约40%(以3-硝基-4-氯苯甲酸计),结构经IR、1H NMR和MS测试技术确证。     

两种生物素杂质的合成

d-生物素(d-B iotin)又称维生素H、辅酶R,以游离或与蛋白质结合的形式广泛分布于动植物组织中,目前生物素已广泛应用于医药、家禽、家畜的营养和饲料添加剂方面[1~4]。目前比较权威的生物素质量标准是欧洲药典[5],其在美国药典[6]的基础上提出了5个有关物质(impurity A、B、C、     

达比加群酯中间体3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯的合成

以对氨基苯腈为起始原料,经胺化反应制得N-(4-氰基苯基)甘氨酸(4);4与N-[3-氨基-4-(甲基氨基)苯甲酰基]-N-2-吡啶-β-丙氨酸乙酯(5)经酰胺化后经闭环反应,合成了达比加群酯的关键中间体——3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯,总收率79.6%,其结构经~1H NMR和ESI-MS确证。     

RP-HPLC determination of midecamycin and related impurities

Summary A method has been developed for separation and quantitation of midecamycin A₁ and related impurities by high-performance liquid chromatography with evaporative light-scattering detection (ELSD). Chromatographic conditions included use of a Diamonsil C₁₈ column; the mobile phase was 52:48 acetonitrile −0.2 mol L⁻¹ ammonium formate solution (adjusted to pH 7.3 with triethylamine) at a flow rate of 1 mL min⁻¹. The column temperature was 35°C, the shift tube temperature of the ELSD was 105°C, and the gas flow rate of the ELSD was 3.0 L min⁻¹. The response factors of midecamycins in HPLC-ELSD were the same; the linear equation wasy=599292.44x+2868618.04,r=0.9979, the linear range was 5–80 μg,RSD=0.21–1.54%, and theLOD andLOQ were 0.36 and 1.2 μg, respectively. The method was simple, quick, and precise and could be used to determine midecamycin and its related impurities directly.     

Separation of salbutamol and six related impurities by packed column supercritical fluid chromatography

Summary A rapid separation of salbutamol sulphate and six related impurities: 5-formyl-saligenin, salbutamol ketone, salbutamol bis ether, isopropyl salbutamol, desoxysalbutamol sulphate and salbutamol aldehyde, has been achieved by employing packed column supercritical fluid chromatography. The effects of temperature, pressure, additive concentration and identity on retention have been studied. The use of a basic additive is necessary in order to elute the compounds and improve the peak shape. The best results were obtained by using a diol column and a gradient of modifier (methanol with 0.5% of n-propylamine).     

Identification,characterization, and high‐performance liquid chromatography quantification of process‐related impurities in vonoprazan fumarate

High‐performance liquid chromatography analysis of vonoprazan fumarate, a novel proton pump inhibitor drug revealed six impurities. These were identified by liquid chromatography with mass spectrometry. Further, the structures of the impurities were confirmed by synthesis followed by characterization by mass spectrometry, NMR spectroscopy, and infrared spectroscopy. On the basis of these data and knowledge of the synthetic scheme of vonoprazan fumarate, the previously unknown impurity was identified as 1‐[5‐(2‐fluorophenyl)‐1‐(pyridin‐3‐ylsulfonyl)‐1H‐pyrrol‐3‐yl]‐N‐methyldimethylamine, which is a new compound. The possible mechanisms by which these impurities were formed were also discussed. A high‐performance liquid chromatography method was optimized in order to separate, selectively detect, and quantify all process‐related impurities of vonoprazan fumarate. The presented method has been validated in terms of linearity, limits of detection, and quantification, and response factors and, therefore, is highly suitable for routine analysis of vonoprazan fumarate related substances as well as stability studies.     

Isolation and characterization of degradation products of citalopram and process-related impurities using RP-HPLC

A reversed-phase high-performance liquid chromatographic method for simultaneous separation and determination of citalopram hydrobromide and its process impurities in bulk drugs and pharmaceutical formulations was developed. The separation was accomplished on an Inertsil ODS 3V (250x4.6 mm; particle size 5 mum) column using 0.3% diethylamine (pH = 4.70) and methanol/acetonitrile (55:45 v/v) as mobile phase in a gradient elution mode. The eluents were monitored by a photodiode array detector set at 225 nm. The chromatographic behavior of all the related substances was examined under variable conditions of different solvents, buffer concentrations, and pH. The method was validated in terms of accuracy, precision, and linearity. The method could be of use not only for rapid and routine evaluation of the quality of citalopram in bulk drug manufacturing units but also for the detection of its impurities in pharmaceutical formulations. Three unknown impurities were consistently observed during the analysis of different batches of citalopram. Forced degradation of citalopram was carried out under thermal, photo, acidic, alkaline, and peroxide conditions. The degradation products and unknown impurities were isolated and characterized by ESI-MS/MS, (1)H NMR, and FT-IR spectroscopy.     

Determination of impurities and counterions of pharmaceuticals by capillary electromigration methods

The review presents a survey of recent applications of high‐performance capillary electromigration methods—capillary zone electrophoresis, nonaqueous capillary electrophoresis, capillary isotachophoresis, micellar electrokinetic chromatography, microemulsion electrokinetic chromatography and capillary electrochromatography—for the determination of impurities of pharmaceuticals, including chiral impurities, for the period 2007–2013. In addition, due to the missing evaluation of the determination of counterions of pharmaceuticals by capillary electromigration methods in the last 20 years, the publications dealing with this topic since 1995 are included in this review. General aspects of both these types of applications of capillary electromigration methods in pharmaceutical analysis are discussed, and detailed experimental conditions used for determination of various chemical impurities and counterions of many particular drugs are described.     

Synthesis of potential impurities of cloxacillin sodium drug substance

The present work describes the synthesis and characterization of six related compounds of cloxacillin sodium ( 1 ) viz penicilloic acid of cloxacillin (2) , (3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl) glycine (Glycine analogue of cloxacillin) (3), CMICAA adduct of cloxacillin (4) , (4S)-2-(carboxy(3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido) methyl)-3-(2-ethylhexanoyl)-5,5-dimethylthiazolidine-4-carboxylic acid (N-2-ethylhexanoyl penicilloic acid of cloxacillin) ( 5 ), N-Acetylated penicilloic acid of cloxacillin ( 6 ), and Cloxacillin Penicillamide (7) . These related compounds are very essential in the process development of cloxacillin sodium and are used as reference standards to determine the quality of the drug substance.     

Characterization of process‐related impurities including forced degradation products of alogliptin benzoate and the development of the corresponding reversed‐phase high‐performance liquid chromatography method

The characterization of process‐related impurities and forced degradants of alogliptin benzoate (Alb) in bulk drugs and a stability‐indicating HPLC method for the separation and quantification of all the impurities were investigated. Alb was found to be unstable under acid and alkali stress conditions and two major degradation products (Imp‐F and Imp‐G) were observed. The optimum separation was achieved on Kromasil C₁₈ (250 × 4.6 mm, 5 μm) using 0.1% perchloric acid (pH adjusted to 3.0 with triethylamine) and acetonitrile as a mobile phase in gradient mode. The proposed method was found to be stability indicating, precise, linear (0.10–75.0 μg/mL), accurate, sensitive, and robust for the quantitation of Alb and its process‐related substances and degradation products. The structures of 11 impurities were characterized and confirmed by NMR spectroscopy, MS, and IR spectroscopy, and the most probable formation mechanisms of all impurities were proposed according to the synthesis route.     

Infrared study of iron impurities in polycrystalline solar grade silicon

In this work the role of Fe impurities introduced in boron doped polycrystalline solar grade silicon is examined by means of low temperature absorption measurements in the far infrared. In particular, the results can be explained in term of formation of boron acceptor-iron donor complexes.     

ICP-MS法测定金属镝中的非稀土杂质

用ICP-MS法对高纯金属镝中10种非稀土杂质Al、Fe、Ni、Ti、Co、Cd、Mn、Pb、Cu、Ba、Mg的测定进行了研究。估算了元素的测定下限；研究了酸度影响；并进行了不同方法的结果对照实验；采用In作内标，方法的加标回收率在80.5%-110.2%之间，相对标准偏差低于12%。     

The determination of impurities in caprolactam by capillary gas chromatography-mass spectrometry

A capillary gas chromatography-mass spectrometry (GC-MS) technique has been developed for the determination of impurities in caprolactam. The residual solution of the crude product extracted by benzene was analyzed. A total of 28 compounds in the residual solution were separated. In comparison with the mass spectra obtained with those published in data tables, 24 compounds of the 28 were identified. The possible origination of these impurities was discussed and could be significant in the industrial control of caprolactam.     

Synthesis and characterization of potential impurities of Vigabatrin-An anti epileptic drug

The present work describes the synthesis and characterization of four potential impurities of Vigabatrin (1 Grant, S. M.; Heel, R. C. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Epilepsy and Disorders of Motor Control. Drugs. 1991, 41, 889-926. doi:10.2165/00003495-199141060-00007[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) namely 2-(2-aminobut-3-enyl)malonic acid (2 Impurities in New Drug Substances Q3A (R2): 2006. www.ich.org/products/guidelines/quality/article/quality-guidelines.html (accessed Aug 16, 2018). [Google Scholar]) (Vigabatrin USP impurity-E), 2-(2-oxo-5-vinylpyrrolidin-1-yl)acetic acid (3 Validation of Analytical Procedures: Text and Methodology Q2 (R1): 2006. www.ich.org/products/guidelines/quality/article/quality-guidelines.html (accessed Aug 16, 2018). [Google Scholar]) (USP Tablets impurity), 4-aminohexanoic acid (4 Maurice, W. G.; Gerard, J. L. 2-Pyrrolidinone Compounds and Processes for Making Same. U.S. Patent 4,235,778, November 25, 1980. [Google Scholar]) and 2,2′-oxo-5,5′-bispyrrolidinyl ether (5 Marie-Christine, D.; Bienayme, H.; Popowycz, F.; Lemaire M. Process for Preparing 4-Amino-5-hexenoic acid From Succinimide. E.P. Patent 2,537,827 A1, June 26, 2011. [Google Scholar]). Compound 4 is a possible process related impurity of 1 where as compound 5 is a process related impurity of 5-ethoxy-2-pyrrolinone (16). All these impurities have a significant impact on the quality of the drug product. This work is extremely useful for generic pharmaceutical industry.     

Synthesis,purification and spectroscopic characterization of potential impurities of hexamethylmelamine

The syntheses and spectroscopic properties (ir, ¹H nmr, ¹³C nmr, uv and ms) of pure samples of 2-chloro-4,6-bis(dimethylamino)-s-triazine 1 , 4,6-dichloro-2-dimethylamino-s-triazine 2 , 4,6-bis(dimethylamino)-s-triazin-2(lH)-one 3 , 4-chloro-6-dimethylamino-s-triazin-2(1H)-one 4 , 6-dimethylamino-s-triazine-2,4(1H,3H)-dione 5 , and 2,4,6-tris(dimethylamino)-s-triazine (altretamine, HMM) are reported. Evidence for enol-keto equilibria are also presented for 3 , in which the enol form exhibits as an H-bonded dimer structure similar to the dimer of organic carboxylic acids.     

A review on synthesis of kaolin-based zeolite and the effect of impurities

Zeolite is extensively synthesized for the application in a large variety of catalysis processes such as ion exchange, hydrocarbon cracking, and organic synthesis. In order to satisfy the serious terms of sustainability that denotes to the reduction of costs and chemical waste, kaolinite-based zeolites were produced from cheap natural resources as against to the conventional process that employs pure sodium silicate and sodium aluminate. This review paper is to highlight the current trends in the synthesis of zeolite. Prior to previous reviews, great concern is focused on the impurities effect on the catalytic performance of kaolinite-based zeolites. This study reveals that the impact of impurities in a catalytic reaction was in fact, underestimated or neglected. For instance, it was found that Fe ion concentration as small as 60 ppm gives significant catalytic output. Hence, a new practice to report the concentration of impurities in the research publication is suggested. This undoubtedly will generate a better interpretation of the catalytic activity from the zeolite framework.     

Segregation of organic impurities in thin electroplated Cu metallizations

This article presents investigations regarding the incorporation of organic impurities in thin electroplated Cu metallizations. RF-GD-OES (radio frequency glow discharge optical emission spectrometry) was used for detection of C and H as indicators for incorporated hydrocarbon molecules. The presented results indicate a fragmentation of incorporated hydrocarbons and their constrict segregation near the Cu surface. The bilateral relationship between incorporated organic impurities and intrinsic stress behavior is associated with the Gorky effect.     

Identification of embrittling trace impurities in tungsten heavy alloys by SIMS

Embrittlement of tungsten heavy alloys is often caused by trace impurities. Heavy alloys containing O, Al and Si, respectively, were mechanically tested and exhibited interfacial embrittlement. SIMS analysis of metallographic sections was found to be a suitable tool for comparative analysis of heavy alloys with different fracture behaviour, the results obtained being not dependent on the fracture mode as is the case e.g. with AES. It was found that oxygen may cause embrittlement at the interfaces even at low overall content, since it is enriched at the phase boundaries tungsten-binder. Al is detrimental if it covers the interfaces rather evenly; grossly inhomogeneous distribution is less harmful. Generally, the distribution of trace elements is much more important than their total amount.