那格列奈的多晶型与溶解度

分别对那格列奈B, H和S三种晶型的溶解度、溶解热进行了测定和计算. 结果表明: 那格列奈的S晶型与临床使用的H晶型溶解度均明显大于B晶型. B, H和S三种晶型的溶解热分别为42.84, 28.44 和29.14 kJ•mol^－1. 此外, 我们还新发现了不同于B, H, S晶型的X2晶型, 并且制备出了无定型的那格列奈.     

BaZr0.45Ce0.45Y0.1O3-δ的合成及其电性能研究

采用高温固相反应制备了电导率高、化学稳定性较好的新型高温质子导体BaZr0.45Ce0.45Y0.1O3-δ材料.运用X射线衍射仪、扫描电子显微镜分别对不同烧结温度试样的晶型、微观形貌进行了表征,并应用IM6e型电化学工作站测定了其不同温度下的阻抗谱.结果表明1600℃为最佳的烧结温度,此温度烧结试样具有最高的电导率,800℃约为1.06×10-2S·cm-1,电导活化能为0.76 ev.     

客体分子所处晶穴结构不同对甲烷水合物稳定性的影响

采用分子动力学方法模拟了SⅠ型甲烷水合物受热分解微观过程,并对水合物分解过程中不同晶穴结构内客体分子对甲烷水合物稳定性的作用进行了研究.通过最终构象、均方位移和势能等性质的变化规律对分别缺失大晶穴和小晶穴中客体分子的2种水合物体系随模拟温度升高稳定性的变化进行了分析.模拟结果显示,随温度的上升,水合物稳定性逐渐下降直至彻底分解;而水合物分解速度与2种晶穴各自部分晶穴占有率相关,不能简单的通过整体晶穴占有率表示.对比相同注热过程中2种水合物体系分解状况,发现位于大晶穴内的客体分子对水合物稳定性影响更大,缺失大晶穴内客体分子的水合物更容易随温度升高而分解.     

氢电弧等离子体法制备纳米钛粒子脱硫性能研究

使用H2 Ar等离子体法制备纳米Ti粒子并用球磨法负载到载体上，500℃焙烧后制成纳米TiO2脱硫催化剂．利用TEM、BET、XRD等手段，对催化剂进行了表征．焙烧后纳米钛粒子主要以金红石型TiO2存在．在不同温度、空速、SO2／CS2和老化条件下，进行CS2的水解实验证明，物理法制备的纳米TiO2／Al2O3催化剂具有较高的耐硫酸盐化中毒能力．     

吸附相反应技术制备TiO2的结晶过程以及光降解气相甲苯

研究了吸附相反应技术制备纳米TiO2的结晶过程, 并探讨了该过程对TiO2光催化活性的影响. 利用XRD测定了不同温度和时间焙烧后TiO2的晶型以及晶粒粒径的变化, 发现即使焙烧温度高达900 ℃, TiO2仍维持纯锐钛矿晶型. 随着焙烧温度的增加, TiO2的晶粒粒径变化不大, 均在7 nm以下, 在焙烧温度高于700 ℃时, 锐钛矿结晶峰的峰面积随温度增加, 峰面积保持不变. 改变焙烧时间基本不影响TiO2的晶型和晶粒粒径, 因而其光催化活性变化也较小. 光降解气相甲苯实验表明, 700 ℃焙烧后样品的催化活性最高, 且优于商用P25光催化剂.     

机械球磨固相化学反应制备AlH3及其放氢性能

以LiAlH4和AlCl3为原料, 采用机械球磨固相化学反应方法制备了铝氢化合物, 通过X射线衍射(XRD)、热分析(TG-DSC)和质谱(MS)分析等方法对反应产物进行分析和表征, 研究了不同球磨时间(4、8、15和20 h)对LiAlH4+AlCl体系的固相反应转变规律﹑合成产物和放氢性能的影响. 研究结果表明, 随球磨时间的增加, 球磨固相反应按3LiAlH4+AlCl3→4AlH3+3LiCl方向进行, 形成了非晶态铝氢化合物AlH3, 球磨20 h时反应基本完全. 球磨产物的放氢动力学特性随球磨时间增加而改善, 其放氢起始温度均低于100 ℃, 最大放氢量达到2.6%-3.6%(H2)(w), 接近反应体系的理论储氢量4.85%(H2)(w). 球磨过程中反应产物形成LiCl·H2O以及少量AlH3发生分解是影响球磨产物最大放氢量的主要因素.     

机械球磨固相化学反应制备AlH3及其放氢性能

以LiAlH4和AlCl3为原料,采用机械球磨固相化学反应方法制备了铝氢化合物,通过X射线衍射(XRD)、热分析(TG-DSC)和质谱(MS)分析等方法对反应产物进行分析和表征,研究了不同球磨时间(4、8、15和20 h)对LiAlH4+AlCl体系的固相反应转变规律合成产物和放氢性能的影响.研究结果表明,随球磨时间的增加,球磨固相反应按3LiAlH4+AlCl3→4AlH3+3LiCl方向进行,形成了非晶态铝氢化合物AlH3,球磨20 h时反应基本完全.球磨产物的放氢动力学特性随球磨时间增加而改善,其放氢起始温度均低于100℃,最大放氢量达到2.6%-3.6%(H2)(w),接近反应体系的理论储氢量4.85%(H2)(w).球磨过程中反应产物形成LiCl·H2O以及少量AlH3发生分解是影响球磨产物最大放氢量的主要因素.     

纳米ZnO室温选择氧化H2S特性的研究

碱式碳酸锌在不同焙烧温度下制得的纳米ZnO具有六方晶系纤锌矿结构，平均粒径为15.4 nm、19.1 nm、22.9 nm和33 nm，以其为脱硫剂，对H2S室温脱硫性能进行了研究。利用XRD和XPS技术对脱硫反应前后的样品进行了表征。实验结果表明，纳米ZnO的脱硫性能随粒径的增大而降低，常温、常压下，260 ℃焙烧的纳米ZnO对H2S有高的去除率，并且H2S可选择性地被氧化为单质硫。     

焙烧温度对LaSrFeMo0.9Co0.1O6催化剂催化甲烷燃烧性能的影响

采用溶胶凝胶法制备LaSrFeMo0.9Co0.1O6,以催化甲烷燃烧为目标反应,研究不同焙烧温度(600、700、800、900℃)对其催化甲烷燃烧性能的影响.通过XRD、BET、H2-TPR及SEM技术对其结构进行表征.结果表明,在不同的焙烧温度下均可形成完整的双钙钛矿晶型,且焙烧温度不同其催化活性不同,随着焙烧温度的升高其催化活性先升高后逐渐降低.当焙烧温度为800℃,样品比表面积为14 m2/g,起燃温度T10％为428℃,T90％为640℃.     

氟氢化钾固-固相变的变温红外光谱测定

氟氢化钾（KHF2）晶体随着温度的升高,在196℃发生可逆的固－固相变,晶型由低对称的西方晶系转变到高对称的立方晶系^[1]。由于氟氢化钾的固－固相变焓高,可应用于热能的贮存^[2],它的高温相可用做高电导率的离子导体^[3]。氟氢化钾的应用强烈依赖于本身的晶体性,因此利用各种光谱、X－射线衍射、热分析等技术手段以及量子化学计算对两种晶相结构的研究已日趋完善^[4,5]。而对于其固－固相变升温过程中的动态测定还未见报道,这是由于一般的实验手段难以对升温过程进行原位跟踪所致。变温红外光变法具有简便、快速、实用等优点,因而成为研究相变的有力工具^[6]。本文采用变温红外光谱技术测定了氟氢化钾在不同温度下的红外光谱,发现当温度升高到固－固相变温度时,氟氢化钾的各个特征吸收峰的位置、强度及峰形均发生较大程度的变化,从而为验证氟氢化钾的固－固相变机理提供了依据。     

Study on Stability of Nateglinide Polymorphism

The stability of three forms of nateglinide, especially S-form and H-form, was determined. S-form was a new crystal structure of nateglinide. Three forms of nateglinide were treated in different conditions, such as in various temperatures, humidity, light and so on.Analysis of their crystal structures was performed by X-ray powder diffraction ( XRD ) and their particle shapes were observed with scanning electron microscope ( SEM ). The results indicated that the stability of S-form of nateglinide is the best among the three forms and their particle shapes are quite difference. S-form is the sheet structure of layer upon layer, H-form looks like a hank of silk lines and B-form is the clubbed shape.     

Effect of decrease in both postprandial blood glucose (PBG) and fasting blood glucose (FBG) levels in normal beagle dogs with nateglinide enteric coated granules and immediate release tablets

Nateglinide is a new quick action/short duration (QRSD) type of oral blood glucose regulator, and nateglinide immediate release tablets are used for patients with mild diabetes under the trade name of Fastic((R)) tablets. In this study, we attempted to determine if it was possible to control both post-prandial blood glucose level (PBG) and fasting blood glucose level (FBG) for moderate or severe diabetes through controlled release of nateglinide. Enteric coated granules were selected for the administration form for controlled release of nateglinide, and three types of enteric coated granules were prepared having dissolution pH values of 5.5, 6.5 and 7.2. The three types of enteric coated granules were each administered separately or the enteric coated granules having an dissolution pH of 6.5 were administered simultaneous to administration of nateglinide immediate release tablets to normal beagle dogs just before feeding followed by measurement of plasma nateglinide concentration, plasma insulin concentration and blood glucose level. In the case of administering enteric coated granules alone (nateglinide: 9 mg/kg), the absorption of nateglinide was confirmed to tend to be delayed as the dissolution pH increased. In the case of an dissolution pH of 5.5, decreases in both PBG and FBG were observed. In the case of dissolution pH values of 6.5 and 7.2, only decrease in FBG was observed. In case of nateglinide immediate release tablets (nateglinide: 9 mg/kg), only decrease in PBG was observed. Decreases in both PBG and FBG were observed in the case of simultaneous administration of dissolution pH 6.5 enteric coated granules and nateglinide immediate release tablets just before feeding (nateglinide: 90 mg/head+60 mg/head). A correlation was observed between plasma nateglinide concentrations and blood glucose levels. On the other hand, there were no correlations observed between changes in plasma insulin concentrations and blood glucose levels. In case of nateglinide immediate release tablets (nateglinide: 150 mg/head), Decreases in both PBG and FBG were observed. However, the nateglinide controlled release formulation is more useful than the nateglinide immediate release tablets from the view point of avoidance of side effect, or of easy control of both PBG and FBG. On the basis of these results, the design of a controlled release formulation that contains nateglinide was suggested to enable control of both PBG and FBG for moderate and severe diabetes patients.     

Development of a New Analytical Method for Determination of Related Components in Nateglinide

An isocratic reverse phase liquid chromatographic (RP-LC) assay method has been developed for the quantitative determination of nateglinide and its related components namely imp-1 and imp-2 in bulk drug and in pharmaceutical dosage form, used for the treatment of type II diabetes mellitus. The developed method is stability indicating and also can be used for stability testing. The chromatographic separation was achieved on C-8, 150 × 4.6 mm, 3.5 μm stationary phase. The LC method employs solution A as mobile phase. Solution A contains a mixture of phosphate buffer pH 3.0: acetonitrile (50:50 v/v). The flow rate was 1.0 mL min⁻¹ and the detection wavelength was 210 nm. In the developed LC method the resolution between nateglinide and its potential impurities namely imp-1 and imp-2 was found to be greater than 5.0. The drug was subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. Considerable degradation was found to occur in acid medium, alkaline medium and oxidative stress conditions. The stress samples were assayed against a qualified reference standard and the mass balance was found close to 99.2%. The developed RP-LC method was validated with respect to linearity, accuracy, precision and robustness.     

Development and validation of a stereoselective HPLC method for the determination of the in vitro transport of nateglinide enantiomers in rat intestine

A simple stereoselective high performance liquid chromatographic method was developed for the determination of the in vitro transport of the enantiomers of nateglinide (N-(trans-4-isopropylcyclohexyl-carbonyl)-phenylalanine) in the rat intestine using a Chiralcel OJ-RH column (150 x 4.0 mm, 5 microm). The effects of the mobile phase composition, pH, the flow rate, and the temperature on the chromatographic separation were investigated. The enantioseparation was achieved at 33 degrees C using a mobile phase containing 100 mM potassium dihydrogen phosphate, pH 2.5, and ACN (32:68 v/v) delivered at a flow rate of 1 mL/min. The analytes were monitored at 210 nm and linearity (r >0.99) was obtained for a concentration range of 0.5-50 microg/mL. The LOD and LOQ were 0.2 and 0.5 microg/mL for the R-enantiomer and 0.2 and 0.8 microg/mL for the S-enantiomer, respectively. Both, the intra- and interday accuracy and precision of the calibration curves were determined. The method was successfully applied to estimate the in vitro passage of the enantiomers and the racemate of nateglinide in duodenum, jejunum, and ileum of rats. Generally, higher concentrations of nateglinide and the S-enantiomer were observed when the racemate was administered compared to administration of the individual enantiomers of nateglinide.     

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.     

The drug interaction potential of berberine hydrochloride when co-administered with simvastatin,fenofibrate, gemfibrozil,metformin, glimepiride,nateglinide, pioglitazone and sitagliptin in beagles

Berberine (BBR) hydrochloride is a traditional Chinese medicine with unique hypoglycemic and lipid-lowering effects discovered in recent years. The combination of BBR with other hypoglycemic drugs and lipid-lowering drugs could become a promising treatment strategy. With the aim of evaluating the potential drug-drug interaction (DDI) based on the pharmacokinetics between BBR and simvastatin, fenofibrate, gemfibrozil, metformin, glimepiride, nateglinide, pioglitazone and sitagliptin in beagles, an UPLC-MS/MS method has been developed and validated. The analytes and internal standards were extracted from plasma samples using a magnetic solid phase extraction technique, and then separated by a Luna® Omega C₁₈ column (20.0 × 2.0 mm, 1.6 μm) with water containing 3 mM ammonium and 0.1% formic acid and acetonitrile containing 3 mM ammonium and 0.1% formic acid as the mobile phase. Validation of the UPLC-MS/MS method was carried out following the criteria of the Chinese Pharmacopeia, mainly including specificity, carryover, calibration curve, crosstalk, precision, accuracy, dilution integrity, matrix effect, recovery and stability. The results showed that all the criteria of the method validation met the Chinese Pharmacopoeia guidelines, and the proposed UPLC-MS/MS method was proven to be sensitive, simple and specific to determine all the analytes in the beagles’ plasma samples simultaneously. Meanwhile, the potential DDI between BBR and simvastatin, fenofibrate, gemfibrozil, metformin, glimepiride, nateglinide, pioglitazone and sitagliptin was confirmed in this paper, especially for simvastatin, fenofibrate, gemfibrozil and glimepiride.     

Comparative studies on physical properties concerned with the stability of unphosphorylated, phosphorylated and proteolytically modified L-type pyruvate kinase from pig liver

A study was made of the effects of some agents on the stability of unphosphorylated pyruvate kinase type L, the enzyme phosphorylated with cyclic 3',5'-AMP-stimulated protein kinase and the subtilisin-modified enzyme form from which the phosphorylatable site had been removed. The phosphorylated pyruvate kinase was found to be the most labile of the enzyme forms at high temperature and in the presence of urea. The circular dichroism spectrum of the phosphorylated enzyme also differed from that of the unphosphorylated and proteolytically modified forms. All three forms of the enzyme showed a high degree of stability over a wide pH range. The unphosphorylated enzyme seemed, however, to be the most sensitive to differences in pH. Only 10% of its maximal activity remained after incubation at pH 10 and 30 degrees C for 30 min, compared with 30% and 75% for the phosphorylated and proteolytically modified forms of the enzyme, respectively. Of the three enzyme forms tested the subtilisin-modified pyruvate kinase was most rapidly inactivated by trypsin. These results taken together suggest that the phosphorylated enzyme has a less ordered structure than the other two enzyme forms studied.     

Study on the bioavailability of nateglinide-hydroxypropyl-beta-cyclodextrin complex capsule in rabbits by liquid chromatographic-tandem mass spectrometry

To evaluate the bioavailability of nateglinide-hydroxypropyl-beta-cyclodextrin (HPCD) complex, a rapid and specific liquid chromatographic-tandem mass spectrometric method was developed and validated to determine nateglinide in rabbit serum. The analyte was extracted from serum samples by liquid-liquid extraction, separated on a Zorbax C(18) column and detected by tandem mass spectrometry with an atmospheric pressure chemical ionization interface. Daidzein was used as the internal standard. The method has a lower limit of quantitation of 0.25 mg/L using 200 micro L serum. The intra- and inter-day relative standard deviations calculated from quality control (QC) samples were below 4%. The inter-day relative error was within 1%. Nateglinide serum concentrations in rabbits given nateglinide-hydroxypropyl-beta-cyclodextrin complex were much higher than those given the free drug. Significant difference was observed in main pharmacokinetic parameters of t(max) and C(max) but not AUC(0-t) between the complex and free drug. It was concluded that the absorption rate of nateglinide-HPCD complex was enhanced, compared with that of nateglinide free drug.     

Simultaneous Chiral Separation of Geometry Isomers and Enantiomers of Nateglinide by Capillary Electrophoresis with Mixture of CD Derivations as Chiral Selector

Abstract

A capillary electrophoresis (CE) method for the simultaneous separation of geometry isomers and enantiomers of nateglinide was built. Several different dyclodextrin (CD) derivatives were tested for the chiral separation of nateglinide, and it was proved that ionic CDs [i.e., carboxymethy-β-CD (CM-β-CD) and sulphonic-β-CD (S-β-CD)] could show better chiral selectivity for both geometry isomers and enantiomers than the neutral CDs. The separation of geometry of both isomers and enantiomers of nateglinide was obtained by CE in a 75-µm i.d. × 60 cm (effective length 45 cm) fused-silica capillary at 11 kV voltage, while 30 mM phosphate (pH = 8.38) acted as running buffer and a mixture of 40 mM S-β-CD + 21 mM CM-β-CD served as chiral selector. The detective wavelength was set at 254 nm.