缬沙坦类似物合成中间产物的捕获(I)(英文)

Valsartan[1], which is a very useful medicine in thetreatment of high-pressure blood, contains a tetrazolegroup. Its analogues exploration and complex actiontoward metal ions still remain very rare. As acontinuation of our in-situ [2 3] cycloaddition betw…     

缬沙坦类似物合成中间产物的捕获(Ⅱ)

In this article we mainly discuss the effect of anion of Lewis acid on the structure of the intermediate in synthesis of valsartan analogue. The crystal belongs to monoclinic system with space group P2₁/c, and a=1.099 9(3) nm, b=1.913 4(5) nm, c=0.977 8(3) nm, β=104.806(4)°, V=1.989 5(9) nm³, D_c=1.708 g·cm^-3, Z=18. CCDC: 629931.     

Two selective HPTLC methods for determination of some angiotensin II receptor antagonists in tablets and biological fluids

Two simple, selective, precise and highly sensitive high‐performance thin‐layer chromatography (HPTLC) methods have been developed and validated for analysis of five angiotensin II receptor antagonists, namely losartan, irbesartan valsartan, candesartan and olmesartan, which are widely used in clinical practice. HPTLC of the drugs was performed on pre‐coated silica gel HPTLC plates 60 F₂₅₄ by development using a mobile phase composed of chloroform–acetone–glacial acetic acid (7.8:1.5:0.7m v/v/v), which was suitable for all of the studied drugs. The first method depended on utilizing reflectance/fluorescence mode for detection while the second method depended on using 2,3,5,6‐tetrachloro‐1,4‐benzoquinone as spraying reagent for the first time to form orange spots scanned at 460 nm. A good linear relationship was obtained over the concentration ranges of 1.2–60 and 360–3000 ng/band while detection and quantification limits were in the ranges of 0.07–0.43, 45.2–140.49 and 0.21–1.29, 137.05–425.74 ng/band for reflectance/fluorescence and reflectance/absorbance methods respectively. The developed methods were applied successfully for their determination in tablets and spiked human plasma for reflectance/fluorescence method with good accuracy and precision, and so can be applied in the pharmacokinetic and bioavailability studies.     

Diode array detection for stability assessment and evaluation of degradation kinetics of newly introduced sacubitril in its supramolecular complex (LCZ696) with valsartan

A newly FDA-approved heart failure therapy (LCZ696, supramolecular complex of sacubitril (SAC) and valsartan (VAL), Entresto?) is analyzed with a stability indicating HPLC–DAD method. For the newly introduced drug, SAC, there is no sufficient information about its stability under various stress conditions. The proposed chromatographic method was applied to the kinetic investigation of the acidic, alkaline, and oxidative degradation of SAC with the estimation of its activation energy and half-life at room temperature by the aid of Arrhenius plots. Kinetic investigation was conducted using either different strengths of HCl, NaOH, and H₂O₂ at one selected temperature or different temperature degrees at one selected reagent strength, for the acidic, alkaline, and oxidative stress conditions. It was found that the pseudo-first-order kinetics was followed at each case. The half-lives at room temperature using 0.1?M HCl, 0.01?M NaOH, and 15% H₂O₂ were found to be 20.50, 2.76, and 51.58?hr. The chromatographic method was achieved using Zorbax Eclipse plus-C18 (4.6?×?250?mm, 5?µm) with isocratic elution of mobile phase composed of acetonitrile and 0.025?M phosphate buffer (pH3) in a ratio of 60:40 (v/v).     

Development and validation of a highly sensitive and robust LC‐ESI‐MS/MS method for simultaneous quantitation of simvastatin acid,amlodipine and valsartan in human plasma: application to a clinical pharmacokinetic study

A high‐throughput, simple, highly sensitive and specific LC‐MS/MS method has been developed for simultaneous estimation of simvastatin acid (SA), amlodipine (AD) and valsartan (VS) with 500 µL of human plasma using deuterated simvastatin acid as an internal standard (IS). The API‐4000 LC‐MS/MS was operated under the multiple reaction‐monitoring mode (MRM) using electrospray ionization. The assay procedure involved precipitation of SA, AD, VS and IS from plasma with acetonitrile. The total run time was 2.8 min and the elution of SA, AD, VS and IS occurred at 1.81, 1.12, 1.14 and 1.81 min, respectively; this was achieved with a mobile phase consisting of 0.02 m ammonium formate (pH 4.5):acetonitrile (20:80, v/v) at a flow rate of 0.50 mL/min on an X‐Terra C₁₈ column. A linear response function was established for the range of concentrations 0.5–50 ng/mL (r > 0.994) for VS and 0.2–50 ng/mL (r > 0.996) for SA and AD. The method validation parameters for all three analytes met the acceptance as per FDA guidelines. This novel method has been applied to human pharmacokinetic study. Copyright © 2009 John Wiley & Sons, Ltd.     

Exploration of chiral drugs as references for chiral discrimination of valsartan and voriconazole by tandem mass spectrometry

The use of mass spectrometry for chiral recognition and quantification has attracted great interest owing to its speed, sensitivity, specificity, and tolerance. However, searching for chiral selectors in chiral analyses using mass spectrometry is still problematic. In this study, chiral drugs could be applied as references for the chiral recognition and enantiomeric quantification of valsartan and voriconazole. Two novel pairs of metal-bound diastereomeric complex ions were detected by mass spectrometry, namely, nickel (II)-bound dimeric ions [Ni^II (2R,5S-emtricitabine) (S-valsartan)-H]⁺ and [Ni^II (2R,5S-emtricitabine) (R-valsartan)-H]⁺ and copper (II)-bound dimeric ions [Cu^II (S,S,S-enalaprilat) (2S,3R-voriconazole)-H]⁺ and [Cu^II (S,S,S-enalaprilat) (2R,3S-voriconazole)-H]⁺. The resulting diastereomers were successfully identified based on the relative intensities of their characteristic fragments using tandem mass spectrometry. The logarithm of the characteristic fragment ion abundance ratio exhibited a good linear relationship with the enantiomeric excess. Density functional theory calculations were also performed to elucidate the mechanism of the structural differences observed in the MS results. This established approach proves that chiral drugs can serve as ligands for the rapid recognition and quantitative analysis of other chiral drugs without a chiral chromatographic column or complex sample pretreatment.     

Glycation alter serum albumin binding of valsartan and nateglinide when studied contemporarily

In this research work, an attempt was made to study alteration in glycated serum albumin binding of valsartan and nateglinide using validated HPLC-UV method and ultrafiltration as in vitro protein binding study model. The chromatographic conditions involved stationary phase Kromasil-100 C18 (100?×?4.6?mm, 3.5?µm) with mobile phase of 10?mM phosphate buffer, acetonitrile, isopropyl alcohol in the ratio of 30:65:5 as isocratic mode at a flow rate of 0.8?mL/min; and the eluent was monitored at 218?nm. Protein precipitation technique was used to extract the drugs from human plasma. The calibration curve was found linear in the range from 50 to 5000?ng/mL. Glycation of human serum albumin was achieved at different concentration levels using D-(+)-glucose and glycated human serum albumin (Gly-HSA) were prepared. Valsartan and nateglinide were not affected the plasma protein binding of each other when studied using HSA. The unbound fraction of valsartan and nateglinide was increased to 10–20 times when spiked with Gly-HSA. About 20% increase in unbound fraction of valsartan was observed when spiked with 10?µg/mL of nateglinide. Furthermore, the unbound fraction of nateglinide was increased nearly to 10% more when incubated with Gly-HSA as compare to recombinant human serum albumin.     

Development of an analytical method for the determination of valsartan in commercial drug and sewage sludge samples by HPLC and evaluation of its stability under simulated gastric conditions

An analytical method was developed for determination of valsartan in commercial drug and sewage sludge samples by HPLC–UV using a single wavelength (250 nm). The effect of different environmental storage conditions on the stability of valsartan was examined for a period of 85 days, after which no degradation was observed. The post oral administration stability of the valsartan was also investigated by testing valsartan under simulated gastric conditions. Results obtained showed that the structure of valsartan was conserved over 3.5-h period. The calibration plot of the study was linear over a wide concentration range with a correlation coefficient of 0.9999. The limit of detection and limit of quantitation were found to be 0.014 and 0.046 µ g mL^?1, respectively. The percentage recovery of valsartan from sewage sludge was found to be 99.8%.     

Improved Synthesis of Valsartan via Nucleophilic Aromatic Substitution on Aryloxazoline

A highly efficient approach to the synthesis of the angiotensin II receptor antagonist valsartan (Diovan), one of the most important agents used in antihypertensive therapy today is described. The formation of the aryl–aryl bond represents the key step of its synthesis, which has been done by simple nucleophelic aromatic substitution on aryloxazoline with good yield and purity.     

Optimization via experimental design of an SPE-HPLC-UV-fluorescence method for the determination of valsartan and its metabolite in human plasma samples

A chemometric approach was applied for the optimization of the extraction and separation of the antihypertensive drug valsartan and its metabolite valeryl-4-hydroxy-valsartan from human plasma samples. Due to the high number of experimental and response variables to be studied, fractional factorial design (FFD) and central composite design (CCD) were used to optimize the HPLC-UV-fluorescence method. First, the significant variables were chosen with the help of FFD; then, a CCD was run to obtain the optimal values for the significant variables. The measured responses were the corrected areas of the two analytes and the resolution between the chromatographic peaks. Separation of valsartan, its metabolite valeryl-4-hydroxy-valsartan and candesartan M1, used as internal standard, was made using an Atlantis dC18 100 mm x 3.9 mm id, 100 angstroms, 3 microm chromatographic column. The mobile phase was run in gradient elution mode and consisted of ACN with 0.025% TFA and a 5 mM phosphate buffer with 0.025% TFA at pH 2.5. The initial percentage of ACN was 32% with a stepness of 4.5%/min to reach the 50%. A flow rate of 1.30 mL/min was applied throughout the chromatographic run, and the column temperature was kept to 40+/-0.2 degrees C. In the SPE procedure, experimental design was also used in order at achieve a maximum recovery percentage and extracts free from plasma interferences. The extraction procedure for spiked human plasma samples was carried out using C8 cartridges, phosphate buffer (pH 2, 60 mM) as conditioning agent, a washing step with methanol-phosphate buffer (40:60 v/v), a drying step of 8 min, and diethyl ether as eluent. The SPE-HPLC-UV-fluorescence method developed allowed the separation and quantitation of valsartan and its metabolite from human plasma samples with an adequate resolution and a total analysis time of 1 h.