New unsaturated polyesters as injectable drug carriers

New unsaturated polyesters of poly(fumaric acid-glycol-sebacic acid) copolymers and poly(maleic anhydride-glycol-sebacic acid) copolymers were prepared by melt polycondensation of the corresponding mixed monomers: sebacic anhydride, fumaric acid or maleic anhydride and glycol. Methyl-methacrylate (MMA) was used as crosslinker and dimer acid was used as thinner.In vitro studies showed that those copolymers are degradable in phosphate buffer at 37 °C and poly(fumaric acid-glycol-sebacic acid) has proper drug release rate as drug carriers. The biocompatibility of poly(fumaric acid-glycol-sebacic acid) copolymers under mice skin was also evaluated; macroscopic observation and microscopic analysis demonstrated that the copolymer is biocompatible and well tolerated in vivo. The injected poly(fumaric acid-glycol-sebacic acid) [molar ratio M_{fumaric acid}:M_glycol:M_{sebacic acid} = 1.75:2.20:0.25] containing 5% adriamycin hydrochloride (ADM) in the mice bearing Sarcoma-180 tumor exhibited a good antitumor efficacy. The volume doubling time (VDT) (18 ± 2.5 days) of the tumor growth by this treatment was longer than that (7 ± 0.9 days) by the subcutaneous injection of ADM.     

Simultaneous Determination of Enalapril and Enalaprilat in Human Plasma by LC-MS: Application to a Bioequivalence Study

A rapid, simple and specific liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) method has been developed and validated for the simultaneous determination of enalapril and its major active metabolite enalaprilat in human plasma. Benazepril hydrochloride was used as the internal standard. Plasma was deproteinized with acetone and centrifuged. The supernatant was transferred and evaporated to dryness and the residue dissolved in mobile phase. Samples were separated on a C18 column with a mobile phase of methanol–20 mM ammonium acetate (53:47, v/v) containing 0.15% trifluoracetic acid (v/v) with a pH of 3.0. Enalapril, enalaprilat and the internal standard were measured by electrospray positive selective ion monitoring mode. The method was validated over a linear range of 1.56–400 ng mL⁻¹ and the limits of quantification were 1.56 ng mL⁻¹ for both enalapril and enalaprilat using 0.1 mL plasma. Extraction efficiency was more than 84% and recoveries were in range of 93.65–101.17%. The intra-day relative standard deviations (RSD) were less than 8.16 and 7.05% and inter-day RSDs were within 8.42 and 5.72% for enalapril and enalaprilat, respectively. The storage stability of QC samples was investigated under various conditions. The method was successfully applied for the evaluation of the pharmacokinetics and bioequivalence of enalapril and enalaprilat in 20 healthy volunteers after an oral dose of 20 mg enalapril maleate.     

纳米银修饰电极差分脉冲伏安法测定盐酸金霉素

建立了快速测定盐酸金霉素(CTC)的方法。通过NaBH4还原法制备纳米银(AgNPs)溶胶,并利用X射线衍射和紫外-可见光谱进行表征。将制备好的AgNPs滴涂到玻碳电极表面制备修饰电极(AgNPs/GCE),研究了CTC在AgNPs/GCE上的电化学行为及伏安法测定,优化了缓冲溶液和pH等检测条件。结果表明,CTC在pH 3.3的柠檬酸-NaOH-HCl缓冲溶液中检测效果最佳。CTC在AgNPs/GCE上发生2个电子和2个质子的不可逆电化学氧化反应,且反应受吸附控制。最佳条件下,CTC的氧化峰电流与其浓度呈现良好的线性关系,线性范围为0.5~100μmol/L,检出限为0.14μmol/L。该修饰电极可用于河水样品检测。     

Validation of a direct non-destructive quantitative analysis of amiodarone hydrochloride in Angoron formulations using FT-Raman spectroscopy

Raman spectroscopy was applied for the direct non-destructive analysis of amiodarone hydrochloride (ADH), the active ingredient of the liquid formulation Angoron^®. The FT-Raman spectra were obtained through the un-broken as-received ampoules of Angoron^®. Using the most intense vibration of the active pharmaceutical ingredient (API) at 1568 cm⁻¹, a calibration model, based on solutions with known concentrations, was developed. The model was applied to the Raman spectra recorded from three as-purchased commercial formulations of Angoron^® having nominal strength of 50 mg ml⁻¹ ADH. The average value of the API in these samples was found to be 48.56 ± 0.64 mg ml⁻¹ while the detection limit of the proposed technique was found to be 2.11 mg ml⁻¹. The results were compared to those obtained from the application of HPLC using the methodology described in the European Pharmacopoeia and found to be in excellent agreement. The proposed analytical methodology was also validated by evaluating the linearity of the calibration line as well as its accuracy and precision. The main advantage of Raman spectroscopy over HPLC method during routine analysis is that it is considerably faster and no solvent consuming. Furthermore, Raman spectroscopy is non-destructive for the sample. However, the detection limit for Raman spectroscopy is much higher than the corresponding for the HPLC methodology.     

An unexpected reaction of 2-(cyclopent-2-enyl)aniline hydrochloride with dimethyldioxirane

An unusual direction of the reaction of 2-(cyclopent-2-enyl)aniline hydrochloride with dimethyldioxirane was found: the formation of two isomeric products,viz., 3- and 6-chloro-2-(cyclopent-2-enyl)anilines, was observed. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1654–1655, August, 1998.     

Application of microcalorimetry to the formulation study

Isothermal microcalorimetry was used to evaluate excipient compatibility of solid dosage form. Oxybutynin hydrochloride and cefaclor were used as model drugs for compatibility test with excipients. The calorimetric data for compatibility test were compared with those of HPLC data. Evaluation of compatibility between drug and excipient of solid dosage form might be possible to use isothermal microcalorimetry instead of conventional method. By using microcalorimetric method, the evaluation of the compatibility between drug and excipient could be successfully performed with a simple operation in a short time. The application of the isothermal microcalorimetry would be useful for the screening test of the drug compatibility with excipients.     

Ferrocenoyl peptides with sulfur-containing side chains: synthesis, solid state and solution structures

The synthesis and full characterization of a number of amino acid and dipeptide derivatives with sulfur-containing side chains derived from ferrocene carboxylic acid and ferrocene-1,1′-dicarboxylic acid is presented. In particular, compounds Fc-CO-(Aaa)_n-OMe (4) and Fe[C₅H₄-CO-(Aaa)_n-OMe]₂ (3) with (Aaa)_n = Cys(Bzl) (a), Cys(Bzl)-Cys(Bzl) (b), Cys(p-OMe-Bzl) (c), Cys(p-OMe-Bzl)-Cys(p-OMe-Bzl) (d), Met (e), and Met-Met (f) were prepared. Also, the free acid derivatives Fe[C₅H₄-CO-Met-OH]₂ (6e) and Fc-CO-Met-OH (7e) were prepared and characterized. The solid state structures of 3a, 4b, and 4e were determined by single crystal X-ray diffraction. Compound 3a shows a 1,3′ substitution pattern on the Cp rings in the solid state. Structures in solution were determined by NMR, IR and CD spectroscopy, with particular emphasis on the question of hydrogen bonding and helical chirality of the metallocene. As an example, the full assignment for the Cp signals in the disubstituted derivative 3a was achieved by simulation of the ¹H NMR signals from the cyclopentadienyl ring in combination with 2D-NOESY spectra. In solution, 3a has the known 1,2′ substitution pattern, which is stabilized by intramolecular hydrogen bonds.     

Optimized POCl3-assisted synthesis of 2-amino-1,3,4-thiadiazole/1,3,4-oxadiazole derivatives as anti-influenza agents

Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl₃-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2-amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl₃ was disclosed. Meantime, to establish a comprehensive structure–activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI·HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC₅₀ values of 3.5 μM and 7.5 μM, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug.     

Conjugate base catalysed one-pot synthesis of pyrazoles from β-formyl enamides

A novel one-pot synthesis of pyrazoles has been accomplished by the reaction of β-formyl enamides with hydroxylamine hydrochloride catalysed by potassium dihydrogenphosphate in acid medium.     

(S)-3-苯基-2-氨基丙硫醇盐酸盐的合成

以L 苯丙氨酸为原料经还原反应得到氨基醇,用Boc基团进行氨基保护后得到(S) 3 苯基 2 叔丁氧羰基氨基 1 丙醇,甲磺酰化后与硫代乙酸钾在DMF中反应得到(S) 3 苯基 2 叔丁氧羰基氨基 1 丙硫醇乙酸酯,再分别脱除乙酰基,氨基保护基后得到(S) 3 苯基 2 氨基丙硫醇盐酸盐.并用元素分析、红外光谱、核磁共振等手段对中间体和目标化合物进行了表征.