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• 2014 Volume 45 Issue 4
  Published: 10 April 2014

    

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  Synthesis of Vortioxetine Hydrobromide

  WANG Fang, XU Hao, WU Xuesong, CEN Junda*

  2014, 45(4): 301-302.

  Abstract ( )   Knowledge map   Save

  Vortioxetine hydrobromide was synthesized from 1-fluoro-2-nitrobenzene by nucleophilic substitution with 2,4-dimethylbenzenethiol to give 2-(2,4-imethylphenylthio)nitrobenzene, which was subjected to Pd/C-catalyzed hydrogenation to afford 2-[(2,4-dimethylphenyl)thio]aniline, followed by condensation with bis(2-chloroethyl)amine hydrochloride and salt formation with an overall yield of about 49％.
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  Preparation and Structural Confirmation of the Related Substances of Rivaroxaban

  CAI Zhengyan, WEN Yingling, ZHANG Shunli, LIU Zhenren, HAO Qun

  2014, 45(4): 303-307.

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  According to the structural characteristics of rivaroxaban and its synthetic process, eight related substances: 5-chloro-N-[[2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide(A), N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide (B), 4,5-dichloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl]methyl]thiophene-2- carboxamide(C), (S)-2-[[[2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl]methyl]carbamoyl]benzoic acid(D), N1,N2-bis-[[(S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl]methyl]phthalamide(E), 5-chloro-N-methylthiophene-2-carboxamide(F), 5-chloro-N,N-dimethylthiophene-2-carboxamide(G) and 1,3-bis-[[(S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-xazolidin-5-yl]methyl]urea(H), were synthesized and confirmed by 1H NMR and MS. These substances were taken as the references for the quality control of rivaroxaban.
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  Preparation of Related Substances of Montelukast Sodium

  李国祥1,2，官程波2，陈万芝1，蒲 通2*

  2014, 45(4): 308-311.

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  To perform the quality control of montelukast sodium, three related substances recorded in EU pharmacopoeia 7.3 were prepared, and their structures were confirmed by IR, 1H NMR, 13C NMR and MS. These substances were [1-[[[(1R)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-methylethenyl)phenyl]propyl]-sulfanyl]methyl]cyclopropyl]acetic acid(B), [1-[[[1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfinyl]methyl]cyclopropyl]acetic acid(C) and [1-[[[(1R)-1-[3-[(Z)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]-
  acetic acid(G).
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  Synthesis of 3,4,5-Trimethoxybenzamides and Antifatigue Activities

  FAN Wutu1, WU Xianglong1, PAN Yalei1, ZHAI Yuankun1, MEI Qibing1,2*

  2014, 45(4): 312-314.

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  A series of noval AMPA receptor modulators, 3,4,5-trimethoxybenzamides(1a - 1e), were synthesized by the esterfication of 3,4,5-trimethoxy benzoic acid with N-succinimidyl-trifluoroacetate, then reacted with nitrogen heterocyclic rings. The antifatigue activities were evaluated by weight-loaded forced swimming test and AMPA receptor binding assay. The results showed that 1a and 1b had potent antifatigue activities. Meanwhile, 1a and 1b also had high affinity with AMPA receptor.
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  Synthesis of (1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamine D-Mandelate

  XU Jianguo1, HE Xiaoqing1, WU Taizhi1, LIU Xiaohua2, ZHANG Fuli1

  2014, 45(4): 315-317.

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   (1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamine [(1R,2S)-1] D-mandelate, the key intermediate of ticagrelor, was synthesized from 1,2-difluorobenzene via Friedel-Crafts acylation, CBS reduction, cyclopropanation, ammonolysis, Hofmann degradation followed by salt formation with D-mandelic acid with an overall yield of
  32％. The enatiomer of (1R,2S)-1 D-mandelate and 1 oxalate were synthesized by the similar procedures, and the analytical method of chiral HPLC was established. The value of enantiomeric excess of (1R,2S)-1 D-mandelate was 99.9％.
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  Optimization of Fermentation Medium for Cephamycin C Production by Response Surface Methodology

  ZHAO Yunxia1, LIN Huimin2, LI Ji'an2, CHEN Daijie1,3*

  2014, 45(4): 318-321.

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  The main notable factors of the fermentation medium for Streptomycin sp. OFR1022 producing cephamycin C (1) were optimized by one factor at-a-time method and Box-Behken design for response surface methodology to optimize the fermentation technology as well as to increase the productivity of 1. The experimental results were examined through regression analysis by Design Expert 8.0. Finally, the optimal medium was obtained and the production of 1 reached to 1 905.6 µg/ml, a 68.3％ increase compared to that of the original medium, with a relative error of 3.95％ to the predicted value (1 984.03 µg/ml).
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  Breeding of Clavulanic Acid-producing Strain

  YU Yanqing, TIAN Min, LIN Ming, JIANG Yong, WANG Kunrong*

  2014, 45(4): 322-324.

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  The protoplast of clavulanic acid-producing strain SIIA 0487 was mutagenized by ultraviolet radiation. A threonine resistance mutant named as SIIA 0220 was obtained on the regeneration medium containing 8％threonine. The tolerance level of threonine increased from 6％ to 10％. The yield of clavulanic acid increased by 36％ in shake flask fermentation compared with the parent strain. Its genetic stability was good.
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  Influence of Micronization of Andrographolide on Micromeritic Properties and Dissolution

  ZHANG Dingkun1, LIN Junzhi2, QIN Chunfeng1, GUO Zhiping3, YANG Ming1,4*

  2014, 45(4): 325-329.

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  The ultrafine powder of andrographolide was prepared by vibromill. The micromeritic properties, solubility and dissolution of the product were compared with those of bulk drug powder. The results showed that the diameter, bulk density and tap density of the powder grinded for 5 min were significantly decreased (P<0.01), while the specific surface area and porosity were significantly increased (P<0.01). There were no significant differences between these two kinds of andrographolide powder in aspects of IR spectrum, DSC curve and apparent solubility in PBS with different pH values. The results of dissolution test showed that the dissolution rate of the ultrafine powder in 0.2％ SDS increased dramatically. These findings indicated that the decrease of the size distribution and the increase of the specific surface area and porosity mainly contributed to the dissolution increase in ultrafine powder.
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  Fingerprint Chromatography of Callicarpa kwangtungensis Chun by UFLC

  LI Li1, YANG Yifang1*, HU Xiao1, XIAO Wei2, WANG Zhenzhong2

  2014, 45(4): 330-333.

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  An UFLC method was used for the establishment of fingerprint chromatography of Callicarpa kwangtungensis Chun and the fingerprint chromatography was performed with chemical recognition mode. An Ultimate XB-C18 column was used with the mobile phase of acetonitrile︰0.5％ phosphoric acid by gradient elution at the detection wavelength of 332 nm. Seventeen common peaks were determined in UFLC fingerprint and were divided into two categories according to the DAD spectrum analysis. The UFLC fingerprint chromatography could distinguish Callicarpa kwangtungensis Chun from the suspected varieties and was effective for its quality control.
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  Refinement of Water Extract of Bushen Yishou Capsules

  WANG Xin1, LUO Weizao1, WANG Aiping1, PENG Tao2, QIN Yao2*

  2014, 45(4): 334-338.

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  The refining process of water extract of Bushen Yishou capsules by Seplite LX-66 macroporous resin was studied. The optimal conditions for the refining process were selected and the renewing and aging conditions of macroporous resin were obtained. With the help of HPLC fingerprint chromatogram of the water extract of Bushen Yishou capsules, ten common peaks and dry extract yield by 70％ ethanol eluting fraction were chosen as the indexes for evaluating the loading amount, elution condition and the renewing and aging conditions of Seplite LX-66 macroporous resin. The results revealed that the optimal conditions for refining process were as follows: sample temperature of 60 ℃, loading amount equal to 2 times of the dry weight of macroporous resin, water and 70％ ethanol eluting volume
  of 2.7 and 2.0 times of the macroporous resin, respectively. The macroporous resin wasn't aged after repeated for 17 batches
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  Preparation of Methotrexate-loaded in situ Gel for Subcutaneous Injection

  ZHAO Huanzhe1, WANG Ting1,2, LIAO Niyan3, DING Jinsong1*

  2014, 45(4): 339-343.

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  The methotrexate-loaded in situ gel for subcutaneous injection based on thermo-sensitive chitosan/glycerophosphate (CS/GP) hydrogel was prepared. The formulation was optimized by central composite design and response surface methodology with amounts of CS and GP as independent variables and the time of gelation and the viscosity as dependent variables. The compositions of the optimal formulation were determined as 1.69％ CS and 13.03％GP. The observed optimized formulation had viscosity of (184.0±12.5)mPa.s, gelation time of (6±2) min and pH value of 7.01±0.05. Moreover, the product could maintain stable within 30 d after lyophilization.
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  Preparation and in vitro/in vivo Evaluation of Levamlodipine Besylate and Losartan Potassium Controlled-release Tablets

  SHI Qide, FENG Zhong*

  2014, 45(4): 344-348.

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  The levamlodipine besylate (1) and losartan potassium (2) controlled-release tablets were prepared. An HPLC method was established for the determination of both drugs in the self-made product. The in vitro release behaviors in different media and the pharmacokinetics in Beagle dogs of the product were also investigated. The fitting results of drug release in vitro showed that both 1 and 2 released from the product within 24 h in different media exhibited a zero-order release profile. The relative bioavailabilities of 1 and 2 were 95.2％ and 90.6％, respectively. The t1/2 of 1and 2 of the self-made product were prolonged to (15.3±4.7)h and (5.1±2.3)h, while those of common prescribed tablets of 1 and 2 were(8.3±2.8)h and (3.1±1.8)h, respectively. It indicated that the self-made product had a controlled-release profile.
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  Preparation of Carbamazepine Particles by Supercritical Anti-solvent Process

  PAN Dingding, YAN Tingxuan,WANG Zhixiang*, HUANG Dechun, DANG Beilei

  2014, 45(4): 349-353.

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  To improve the dissolution of carbamazepine (1), the particles were prepared by supercritical antisolvent process with acetone as solvent. With particle size as the evaluation index, the preparation process was optimized by single factor experiment and orthogonal design. The optimal particles were prepared under the process conditions of solution volumetric flow rate of 1.0 ml/min, pressure of 8 MPa, temperature of 50 ℃ and 1 mass concentration of 16 mg/ml. The prepared particles were characterized by SEM, IR, DSC and XRD, the in vitro dissolution test was also conducted. The results showed that the average particle size of the optimal product was 5.9 µm with I crystal form and narrow particle size distribution. Although the dissolution rate of the particles was lower than the bulk drug in the initial
  phase, but it was notably accelerated and finally the dissolution was about 70.8％ at 240 min, which was significantly higher than the bulk drug of 43.7％.
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  Comparative Study on Oral Bioavailability of Cyclosporine A-loaded Solid Dispersion and Nanosuspension

  WANG Kai1,2, LU Yi2, QI Jianping2, YIN Zongning1*, WU Wei2

  2014, 45(4): 354-358.

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  Cyclosporine A-loaded solid dispersion and nanosuspension were prepared by fluid-bed coating technique and precipitation-ultrasonication method, respectively. The formulation of nanosuspension was optimized by single factor test with particle size and polydispersity as indicators. The optimal nanosuspension was prepared with the ratio cyclosporine A to Poloxamer 407 of 1∶1 and ethanol as organic solvent under the ultrasonic powder of 540 W for 1 min. The in vitro dissolution and in vivo absorption in Beagle dogs of solid dispersion and nanosuspension were investigated. The results showed that the dissolution rates of the prepared solid dispersion and suspension were both faster than that of the bulk drug. The drug dissolution from the two preparations achieved to 90％ at 30 and 40 min, respectively. The pharmacokinetics in Beagle dogs showed that the relative bioavailabilities of solid dispersion and nanosuspension were 70.8％ and 25.2％, compared with Sandimmun Neoral. It indicated that the absorption enhancing effect of solid dispersion was superior to nanosuspension.
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  Comparison of Two Specifications for Transdermal Gel of Donepezil Hydrochloride

  WANG Xue1, LUO Huafei1, WU Yubo1, WANG Hao2, ZHOU Bin2*

  2014, 45(4): 359-363.

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  Two specifications for transdermal gel of donepezil hydrochloride (specification 1: 22.4 mg/g; specification 2: 11.4 mg/g)were prepared by swelling method. The transdermal effect through the excised nude mouse skin, appearance, viscosity, pH value and metered mass of the two specifications products were evaluated, respectively. The difference of the pharmacokinetic behaviors of the two products in rats after transdermal administration of equal dose, which meant that the area of specification 2 was double, was compared. Both products had good appearance. The cumulative permeation amounts at 24 h for specification 1 and 2 were (574.4±57.1) and (498.4±2.3)µg/cm2, and the pH values were 8.02±0.08 and 8.01±0.04, respectively. The metered mass of the two gels were(447.1±1.5) and (446.0 ±1.8)mg. The results of pharmacokinetics showed that the AUC0→t and cmax for specification 2 were higher than those of specification 1 (P=0.10). It indicated that the AUC could be increased by reducing the drug content in gel and increasing its administration area.
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  Determination of Glucosamine by Precolumn Derivative HPLC and Its Percutaneous Absorption in vitro

  GAO Junwei1,2, ZHANG Jiquan1,2, WU Fei1,2, LIU Chunlin1,2, RUAN Kefeng1,2*

  2014, 45(4): 364-366.

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  An HPLC method was established for the determination of glucosamine, and the glucosamine permeating through the rat skin in vitro was evaluated. Dansyl chloride was used as derivatization reagent. A C18 column was used with the mobile phase of water︰acetonitrile (70︰30) at the detection wavelength of 250 nm. The calibration curve was linear in the concentration range of 10 - 1 000 µg/ml. Its recovery was 101.8％, with RSD of 2.41％. The penetration experiment in vitro with the skin of rat was performed on modified Franz diffusion cells. The percutaneous rate and the permeability coefficient of glucosamine were calculated as 42.110 µg·cm-2·h-1 and 1.610×10-4 cm·h-1, respectively.
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  Determination of Residual Tetracycline in PEG-interferon α-2a Injection by HPLC

  Xü Mingming, ZHENG Luxia, SHAO Hong, WU Lihong, CHEN Gang*

  2014, 45(4): 367-369.

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  An HPLC method was established for the determination of residual tetracycline in PEG-interferon α-2a injection. A SEC column was used with the mobile phase of 0.01 mol/L sodium dihydrogen phosphate solution-0.2 mol/L lithium chloride buffer at the detection wavelength of 360 nm. The calibration curve was linear in the
  concentration range of 18 - 240 ng/ml. The recoveries were 99.9％ - 101.6％, with RSD of 1.4％.
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  Determination of Three Effective Components in Compound Chlortetracycline Film by HPLC

  WANG Pengyuan1, ZHANG Taoli1, PANG Yongbo2, GU Yi1, WANG Xiaojuan1*

  2014, 45(4): 370-373.

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  An HPLC method was established for the determination of chlortetracycline hydrochloride, dyclonine hydrochloride and prednisone acetate in compound chlortetracycline film. A Diamonsil C18 column was used, with the mobile phase of acetonitrile︰0.2％ phosphoric acid by gradient elution at the detection wavelength of 254 nm. The calibration curves for chlortetracycline hydrochloride, dyclonine hydrochloride and prednisone acetate were linear in the ranges of 40.0 - 120.0, 15.0 - 45.0 and 5.0 - 15.0 µg/ml, respectively. Their average recoveries were 101.0％, 100.1％ and 100.3％, with RSDs of 0.91％, 1.3％ and 1.1％, respectively.
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  Determination of Loganin in Fructus corni by Near Infrared Spectroscopy

  GONG Haiyan1, LI Shan2, XIE Caixia1, LEI Jingwei1, BAI Yan1*

  2014, 45(4): 374-376.

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  A near infrared diffuse reflection spectroscopy method was established for the rapid determination of loganin in Fructus corni. The NIR spectra of the powdered Fructus corni were collected, and the partial least squares (PLS) was developed to correlate the spectra and the corresponding HPLC values. The correlation coefficient (R2) of the calibration model for loganin was 0.958 95, while root mean square error of calibration(RMSEC), root mean square error of cross validation(RMSECV) and root mean square error of predication(RMSEP) were 0.034 4, 0.062 5 and 0.094 8, respectively.
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  Preparation, Characterization and Transformation of Esomeprazole Magnesium Polymorphs

  LIN Qing, LU Jie*, ZHOU Xun, WU Danhui

  2014, 45(4): 377-380.

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  In this paper, the esomeprazole magnesium polymorphs (dihydrate form A, dihydrate form B, tetrahydrate and trihydrate) were prepared. The polymorphs were characterized by powder X-ray diffraction, infrared spectroscopy and thermal gravimetric analysis. The identification of different polymorphs together with the conditions among their transformation was established.
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  Research Progress on Molecular Imprinting Technology Based Enantioseparation and Enantioselective Drug Delivery Systems of Chiral Drugs

  RONG Yi, ZHANG Liang, YU Wenying, YE Jincui*

  2014, 45(4): 381-386.

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  Molecular imprinted polymers (MIPs) with high selectivity and affinity for the template molecules are synthetic materials which mimic natural molecularly recognition system. MIPs prepared by the single enantiomer as template show enantioselective recognition capabilities due to their special structures of the three-dimensional cavities, and the applied research in the field of chiral drugs have been developed rapidly. This paper provides an overview on the recent advances in applications of MIPs to chiral stationary phases for the enantioseparation of chiral drugs, as well as the usage for the enantioselective intelligent drug delivery systems as excipients.
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  Progress on Physical Properties of Wet Mass in Extrusion-spheronization Process

  ZHANG Xue1,2, HONG Yanlong1,2*, XIAN Jiechen1,2, FENG Yi1,2, XU Desheng1,3

  2014, 45(4): 387-391.

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  Extrusion-spheronization process has become one of the mostly used methods for the preparation of pellets at home and abroad. The formulation parameters (such as physicochemical properties of dry powders and wet mass) and the process parameters are associated mainly with the quality of pellets, and physical properties of wet mass have been found to have significant influence on formability of the resultant pellets. Therefore, the physical properties and characterization of wet mass as well as the association with the formability of pellets are reviewed on the basis of literatures at home and abroad.
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  Research Progress of Metabolic Pathway Engineering of ω-3 PUFAs

  ZHANG Qi, HU Youjia, XIE Liping*

  2014, 45(4): 392-397.

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  ω-3 polyunsaturated fatty acids (ω-3 PUFAs) are taken seriously for its important role in human health. More and more ω-3 PUFAs are needed for its ideal prephylaxis and treatment effects on immune system, cardiovascular system and nervous system diseases. However, the resource of ω-3 PUFAs is relatively scarce because it was mainly extracted from fish oil which is polluted by toxic substances such as heavy metals and dioxins. Therefore, it is urgent to find new sustainable resources to produce ω-3 PUFAs. With the development of modern biotechnology, through metabolic pathway engineering to improve the production of ω-3 PUFAs becomes possible. In this review, we mainly elaborated the research progress of metabolic pathway engineering of ω-3 PUFAs