New Synthesis of Analogues of the Antihypertensive Active Pharmaceutical Ingredient Irbesartan

A simple and new synthetic approach to various analogues of Irbesartan is described.     

Novel Synthesis and Characterization of Irbesartan Derivative an Anti-Hypertensive Active Pharmaceutical Ingredient (API)

The current research focuses on the design, method development, characterization, and clinical assessment of novel irbesartan medication compounds. The objective of synthetic modification of a drug molecule is to achieve the desired properties such as enhancing the pharmacological properties and minimizing the side effects. It is a biphenyl tetrazole and an aza-spiro compound, a highly selective, potent nonpeptide compound that belongs to the sartan group, an authorized type-1 angiotensin II receptor (AT1), dilates the blood vessels and is used in curing of to treat high blood pressure, cardiac arrest, and renal disease in diabetics. To achieve the structural modification of the irbesartan drug, the researcher prepared the FeCl₃/SiO₂ catalyst and successfully used it for the acetylation, chloro acetylation reaction of irbesartan with acetyl chloride and chloroacetyl chloride. Further, the reaction is performed in presence of the catalyst and without a catalyst to elucidate the role of the catalyst. With the aid of TLC, FT-IR, and UV–visible spectral methods, the structural interpretation of synthesized derivatives is completed. The present work illustrates a novel method of synthesis of irbesartan derivatives through safe and convenient procedures. The pharmacological evaluation of synthetic derivatives and green chemistry protocol of synthesis is under progress.     

A Short and Simple Synthesis of Ketene Acetals

A novel and convenient synthesis of ketene acetals 1a-g in moderate to good yield has been achieved starting from acetonitrile by using Pinner reaction approach.     

Synthesis and Spectral Characterization of Related Substances of Lacidipine,an Antihypertensive Drug

Five related substances (impurities) were detected in lacidipine bulk drug substance by a simple high-performance liquid chromatographic method (HPLC) and were identified by liquid chromatography–mass spectrometry (LC-MS). These related substances were independently synthesized, characterized, and co-injected with the sample containing impurities.     

Enantioselective Organophotocatalytic Telescoped Synthesis of a Chiral Privileged Active Pharmaceutical Ingredient

The continuous flow, enantioselective, organophotoredox catalytic asymmetric alkylation of aldehydes was studied, by using a homemade, custom-designed photoreactor for reactions under cryogenic conditions. Going from microfluidic conditions up to a 10 mL mesofluidic reactor, an increase of productivity by almost 18000 % compared to the batch reaction was demonstrated. Finally, for the first time, a stereoselective photoredox organocatalytic continuous flow reaction in a fully telescoped process for an active pharmaceutical ingredient (API)synthesis was successfully achieved. The final process consists of four units of operation: visible light-driven asymmetric catalytic benzylation under continuous flow, inline continuous work-up, neutralisation and a final oxidative amidation step afforded the pharmaceutically active molecule in 95 % e.e.     

Synthesis of Active Metabolites of Carvedilol,an Antihypertensive Drug

A simple synthetic route for active metabolites of carvedilol is reported. The metabolites 4′-hydroxycarvedilol and 5′-hydroxycarvedilol have exhibited high activity for β-blockade. We have disclosed syntheses of 4′-hydroxycarvedilol and 5′-hydroxycarvedilol from commercially available vanillin and isovanillin, respectively.     

Looking Beyond the Column: An Investigation into Method Irreproducibility for an Active Pharmaceutical Ingredient

Irreproducibility during initial development of a high performance liquid chromatography method is seldom investigated in a thorough and careful manner when working in an industrial setting. For a drug project in the early developmental stages, the LC method is often changed, sometimes drastically, if one encounters irreproducibility in the method. Too often a method is deemed irreproducible due to column lot variability, diluent effects, or pH effects with little or no experiments taking place for justification and little thought given to why the irreproducibility may have occurred in the first case. In this paper, a case study is presented in which a systematic approach was carried out in order to determine the exact reason why method irreproducibility was occurring. The findings of the investigation were then drawn onto change a method with poor reproducibility into one that is rugged without the need to start from the beginning and develop a new method.

     

Looking Beyond the Column: An Investigation into Method Irreproducibility for an Active Pharmaceutical Ingredient

Irreproducibility during initial development of a high performance liquid chromatography method is seldom investigated in a thorough and careful manner when working in an industrial setting. For a drug project in the early developmental stages, the LC method is often changed, sometimes drastically, if one encounters irreproducibility in the method. Too often a method is deemed irreproducible due to column lot variability, diluent effects, or pH effects with little or no experiments taking place for justification and little thought given to why the irreproducibility may have occurred in the first case. In this paper, a case study is presented in which a systematic approach was carried out in order to determine the exact reason why method irreproducibility was occurring. The findings of the investigation were then drawn onto change a method with poor reproducibility into one that is rugged without the need to start from the beginning and develop a new method.     

Validated Stability-Indicating Chromatographic Method for the Assay of Erlotinib Active Pharmaceutical Ingredient

Abstract

A simple stability-indicating high-performance liquid-chromatographic (HPLC) method for the assay of erlotinib in the presence of its degradation products was developed on a C18 column using a mobile phase of 0.01 M ammonium formate–acetonitrile–containing formic acid with a flow rate of 1.0 mL min^?1. The method was validated. Selectivity was validated by subjecting the stock solution of erlotinib to acidic, basic, photolysis, oxidative, and thermal degradation. The linearity range and values for limits of detection (LOD) and quantification (LOQ) were found to be 1–198, 0.33, and 1.1 µg mL^?1, respectively. The analysis of the tablets containing erlotinib was quite precise (relative standard deviation <1%).     

Synthesis of 3,5-O-Benzylidene-2-deoxy-L-riboaldose from 5,5-Dihydroxy-2-phenyl-1,3-dioxane

The asymmetric alkylation of 2-phenyl-1,3-dioxan-5-one was achieved via the RAMP-hydrazone. Regeneration of the ketone followed by setreoselective reduction and ozonolysis, gave the protected 2-deoxy-L-ribose, 3,5-O-benzyldiene-2-deoxy-L-erythro-pentoaldose with 98% e.e. Removal of the benzylidene yielded the unnatural 2-deoxy-L-ribose.     

Synthesis and Characterization of Metabolites and Potential Impurities of Lansoprazole,an Antiulcerative Drug

Lansoprazole (Prevacid) is an antiulcerative drug used for the treatment of duodenal and gastric ulcers, reflux oesophagitis, and Zollinger–Ellison syndrome. During the bulk synthesis of lansoprazole, we have observed five impurities: lansoprazole N-oxide, lansoprazole sulfone N-oxide, lansoprazole sulfide, lansoprazole sulfone and N-aralkyl lansoprazole. The present work describes the synthesis and characterization of these impurities.     

过程分析技术(PAT)在原料药生产中的应用

该文通过采用近红外光谱分析技术对原料药(API)的浓度调节过程进行实时监控,介绍了在良好生产规范条件下过程分析技术(PAT)的实施过程。利用偏最小二乘算法开发出两个校正模型分别用以监控原料药和水分含量,并通过模型校正均方根误差(RMSEC)、交叉检验均方根误差(RMSECV)和预测均方根误差(RMSEP)以及对应的决定系数(R²)来评估模型的性能。为保证模型性能,按照分析方法验证要求对模型的线性和范围、准确性、精密度(重复性)、专属性以及稳健性指标进行验证。最后通过系统性能测试确认检测系统满足商业化运行的要求。结果显示,采用过程分析技术控制浓度调节过程,可以大幅度缩短浓度调节时间,节约蒸汽能耗和检测费用,减少生产过程中的偏差,提升产品工艺水平和批次间一致性。     

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、     

Characterizing Active Pharmaceutical Ingredient Binding to Human Serum Albumin by Spin‐Labeling and EPR Spectroscopy

Drug binding to human serum albumin (HSA) has been characterized by a spin‐labeling and continuous‐wave (CW) EPR spectroscopic approach. Specifically, the contribution of functional groups (FGs) in a compound on its albumin‐binding capabilities is quantitatively described. Molecules from different drug classes are labeled with EPR‐active nitroxide radicals (spin‐labeled pharmaceuticals (SLPs)) and in a screening approach CW‐EPR spectroscopy is used to investigate HSA binding under physiological conditions and at varying ratios of SLP to protein. Spectral simulations of the CW‐EPR spectra allow extraction of association constants (K_A) and the maximum number (n) of binding sites per protein. By comparison of data from 23 SLPs, the mechanisms of drug–protein association and the impact of chemical modifications at individual positions on drug uptake can be rationalized. Furthermore, new drug modifications with predictable protein binding tendency may be envisaged.     

Synthesis and Characterization of Metabolites and Potential Impurities of Balsalazide Disodium,an Anti-Inflammatory Drug

Balsalazide disodium (Colazide®) is an oral prodrug of mesalamine (5-aminosalicylic acid) and possesses anti-inflammatory properties. During the process development for balsalazide disodium, we observed eight impurities, namely des-β-alanine balsalazide, balsalazide β-alanine, balsalazide 3-isomer, decarboxy balsalazide, bis-azo salicylic acid, biphenyl-azo salicylic acid, bis-azo diacid, and bis-azo triacid. The present work describes the synthesis and characterization of these impurities.     

NMR Assignments of Six Asymmetrical N-Nitrosamine Isomers Determined in an Active Pharmaceutical Ingredient by DFT Calculations

N-nitrosamines, which are well-known pro-mutagens, are found in drugs, pickled food and tobacco. Therefore, controlling their concentrations is very important. When an HPLC, GC or NMR analysis is conducted to investigate certain asymmetrical N-nitrosamines, two sets of signals attributed to the asymmetric N-nitrosamine isomers are usually observed. However, few reports on the NMR assignment of asymmetrical N-nitrosamine isomers have been published. In this study, we investigated the NMR assignments of the Z/E isomers of six asymmetrical N-nitrosamines by means of density functional theory (DFT) calculations. The configuration of the major isomer of asymmetrical N-nitrosamine 3 was the Z-configuration. The configuration of the major isomers of asymmetrical N-nitrosamines 4–7 was the E-configuration. Then, we determined the Z/E ratios of these asymmetrical N-nitrosamines by means of variable temperature (VT) and room temperature (RT) ¹H-NMR experiments. The ratios of the Z/E isomer 3 quickly increased beyond 100% in the VT ¹H NMR experiments. The ratios of Z/E isomers 4–7 were increased in the range of 10–60% in the VT ¹H NMR experiments. The results of this study indicate that identifying the isomers of asymmetrical N-nitrosamine is necessary to control the quality of N-nitrosamines for active pharmaceutical ingredients (APIs).     

UPLC Method for Determination of Moxonidine and Its Degradation Products in Active Pharmaceutical Ingredient and Pharmaceutical Dosage Form

A simple, rapid, isocratic, stability-indicating reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed and validated for the routine analysis of moxonidine in the presence of its degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms. Forced degradation studies were performed according to the guidance of International Conference for Harmonization and were used to evaluate moxonidine intrinsic stability. The drug was subjected to acid, neutral and base hydrolysis as well as to oxidative, thermal and photolytic decomposition in both solution and solid state. The drug appeared to be unstable towards acid and base hydrolysis. To achieve desirable conditions for UPLC analysis, the method development was done with the assistance of experimental design and multivariate optimization methodology by means of Derringer’s desirability function. Stress samples were analyzed according to the experimental plan for fractional factorial screening design and Box-Behnken optimization design. The chromatographic separation was achieved on a C₁₈ Hypersil Gold aq. column (100 mm × 2.1 mm, 1.9 μm) with the mobile phase consisting of methanol–ammonium acetate buffer (10 mM, pH 3.43) mixture (0.9:99.1, v/v) pumped at a flow rate of 870 μL min^?1 and detection wavelength of 255 nm. The UPLC–MS and UPLC–MS/MS analyses were further used to characterize the found degradation products. The validation of the proposed method was also performed considering selectivity, linearity, accuracy, precision, limit of detection and limit of quantification, and the results indicated that the method fulfilled all required criteria. The method was successfully applied to the analysis of commercial tablets.     

替格瑞洛的合成工艺改进

以2-丙硫基-4,6-二氯-5-氨基嘧啶(3)、2-[((3aR,4S,6R,6a S)-6-氨基-2,2-二甲基四氢-3a H-环戊基[d][1,3]二氧-4-基)氧]-1-乙醇L-酒石酸盐(4)为起始原料,经亲核取代、环合、与(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐(2)发生亲核取代、稀盐酸脱保护制得抗血小板药替格瑞洛,所得目标经1H NMR及MS确证,总收率为65%。     

抗高压药马西替坦的合成及工艺优化

以4-溴苯乙酸甲酯为起始原料,经碳负离子亲核取代、关环、氯代、氮负离子亲核取代、氧负离子亲核取代等6步反应制得抗高血压药马西替坦,并对合成工艺进行了优化。优化后的工艺使中间体的纯度得到了提高,操作更加简便,更有利于工业化生产。中间体和产物的结构均经~1H-NMR和ESI-MS确证。     

Cyclodextrin Complexed Lipid Nanoparticles of Irbesartan for Oral Applications: Design,Development, and In Vitro Characterization

Irbesartan (IR) is an angiotensin II receptor antagonist drug with antihypertensive activity. IR bioavailability is limited due to poor solubility and first-pass metabolism. The current investigation aimed to design, develop, and characterize the cyclodextrin(s) (CD) complexed IR (IR-CD) loaded solid lipid nanoparticles (IR-CD-SLNs) for enhanced solubility, sustained release behavior, and subsequently improved bioavailability through oral administration. Based on phase solubility studies, solid complexes were prepared by the coacervation followed by lyophilization method and characterized for drug content, inclusion efficiency, solubility, and in vitro dissolution. IR-CD inclusion complexes demonstrated enhancement of solubility and dissolution rate of IR. However, the dissolution efficiency was significantly increased with hydroxypropyl-βCD (HP-βCD) inclusion complex than beta-CD (βCD). SLNs were obtained by hot homogenization coupled with the ultrasonication method with IR/HP-βCD inclusion complex loaded into Dynasan 112 and glycerol monostearate (GMS). SLNs were evaluated for physicochemical characteristics, in vitro release, differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and physical stability at room temperature for two months. The optimized SLNs formulation showed particle size, polydispersity index, zeta potential, assay, and entrapment efficiency of 257.6 ± 5.1 nm, 0.21 ± 0.03, −30.5 ± 4.1 mV, 99.8 ± 2.5, and 93.7 ± 2.5%, respectively. IR-CD-SLN and IR-SLN dispersions showed sustained release of IR compared to the IR-CD inclusion complexes. DSC results complimented PXRD results by the absence of IR endothermic peak. Optimized IR-CD complex, IR-SLN, and IR-CD-SLN formulations were stable for two months at room temperature. Thus, the current IR oral formulation may exhibit improved oral bioavailability and prolonged antihypertensive activity, which may improve therapeutic outcomes in the treatment of hypertension and heart failure.