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• 2013 Volume 44 Issue 7
  Published: 10 July 2013

    

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  Synthesis of Imatinib Mesylate

  GUO Jialin1,2, YANG Yihong1, XIAO Junhai2*

  2013, 44(7): 644-647.

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  Imatinib mesylate was synthesized by reaction from 3-acetylpyridine(2) and N,N-dimethylformamide dimethyl acetal(3) to give 3-dimethylamino-1-(3-pyridinyl)-2-propylene-1-one(4), which was subjected to cyclization, reduction, acylation with 4-chloromethylbenzoyl chloride and reaction with N-methylpiperazine, followed by salt formation with an overall yield of about 58％(based on 2).
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  Synthesis of Related Substances of Venlafaxine Hydrochloride

  YU Xufeng, YANG Kai, CHAI Jian, ZHANG Chao, HONG Haiwen

  2013, 44(7): 648-651.

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  To perform the quality control of antidepressant venlafaxine hydrochloride, six related substances recorded in EP 5.5 were prepared, and their structures were confirmed by 1H NMR and MS. These substances were 2-(4-methoxyphenyl)-N,N-dimethylethanamine(A), 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol(C), 1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol(D), 5-(4-methoxyphenyl)-3-methyl-1-oxa-3-azaspiro[5.5]undecane(E), 2-(cyclohex-1-enyl)-2-(4-methoxyphenyl)-N,N-dimethylethanamine(F), and 2-cyclohexyl-2-(4-methoxyphenyl)-N,N-dimethylethanamine(G).
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  Synthesis of Dabigatran Etexilate

  CHEN Yu, ZHU Wei, LIANG Jun, CHEN Huansheng

  2013, 44(7): 652-654.

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  In the presence of CDI, the reaction of 4-methylamino-3-nitrobenzoic acid with ethyl 3-(pyridin-2-ylamino)propanoate produced ethyl 3-[(4-methylamino-3-nitrobenzoyl)(pyridin-2-yl)amino]propanoate. It was reduced by zinc to afford ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propanoate, which was reacted with [(4-cyanophenyl)amino] acetic acid to give ethyl 3-[[2-[(4-cyanophenylamino)methyl]-1-methyl-1H-benzimidazol-5-carbonyl](pyridin-2-yl)amino]propanoate in the presence of CDI, followed by acetic acid in one-pot. Dabigatran etexilate was finally synthesized by amidination and acylation with an overall yield of about 48％.
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  Synthesis of Phosphocreatine Disodium

  LIAN Meihua

  2013, 44(7): 655-657.

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  Phosphocreatine disodium was synthesized from creatinine by phosphorylation to obtain N-(4,5-dihydro-1-methyl-4-oxo-1H-imidazo-2-yl)aminophosphonic dichloride, which was subjected to hydrolysis with sodium bicarbonate and then cleavage of the lactam cycle in the presence of sodium hydroxide with an overall yield of about 51％ and purity of 99.65％.
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  Synthesis of Entecavir

  YANG Shouning1, ZHANG Lei2, HU Wenhao1, YANG Liping1*

  2013, 44(7): 657-659.

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  Entecavir was synthesized from (1S,2S,3S,5S)-3-benzyloxy-5-[6-benzyloxy-2-(tritylamino)-9H-purin-9-yl]-2-(benzyloxymethyl)-cyclopentanol by oxidation with TEMPO/I2 in the presence of NaHCO3, and methylenation with Mg/TiCl4/DCM/THF to give (1S,3R,4S)-N-triphenylmethyl-6-benzyloxy-9-[[2-methylene-4-
  benzyloxy-3-(benzyloxy)methyl]cyclopentyl]-9H-purin-2-amine(4), which was subjected to deprotection with BCl3/MeOH/H2O with an overall yield of about 44％.
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  Synthsis of Substituted 1,3-Dihydroindolin-2-ones

  ZHOU Feng, ZHENG Canhui, ZHU Ju, LIU Jia, ZHOU Youjun*

  2013, 44(7): 660-662.

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  The substituted 1,3-dihydroindo-2-one compounds 1a - 1k, the intermediates of tyrosine kinase inhibitors such as sunitinib, were synthesized from substituted anilines by acylation and cyclization to give substituted isatin derivatives 4a - 4k, followed by reduction with triethylsilane/trifluoroacetic acid.
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  Chemical Constituents of the Residue of Pollen of Brassica campestris L.

  LU Guoqing1, FAN Siyang1, YANG Yifang1*，XIAO Wei2, WANG Zhenzhong2

  2013, 44(7): 669-673.

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  Column chromatography and preparative liquid chromatography were used for the isolation and purification of the chemical constituents of ethanol extract of the residue of the pollen of Brassica campestris L. after extraction by supercritical CO2. Eleven compounds were identified by means of MS and NMR spectroscopy as: uridine (1), isorhamnetin (2), quercetin (3), naringenin (4), kaempferol (5), kaempferol-3-O-β-D-glucopyranoside (6), kaemperferol-3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside (7), isorhamnetin-3-O-α-L-rhamnosyl-(1→2)-β-D-glucopyranoside (8), kaempferol-3-O-(2"-O-α-L-rhamnopyranosyl-3"-β-D-glucopyranosyl)-β-D-glucopyranoside (9), N1,N 5-di- [(E)-p-coumaroyl]-spermidine (10) and N1,N5,N10-tricaffeoyl-spermidine (11). Among them, compounds 8 - 11 were first reported to be isolated from Brassica campestris L..
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  In vitro Deposition Behaviors of Tiotropium Bromide Inhalation Solution in Three Mouth-throat Models

  WANG Jian, WANG Wei, CHEN Fang

  2013, 44(7): 677-680.

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  The in vitro deposition behavior of tiotropium inhalation solution after atomized by a vibrating-mesh nebulizer was investigated with three mouth-throat models. The mouth-throat models, patterns of inhalation airflow and inner coating on the models could significantly influence the deposition. The amount of tiotropium bromide deposited in idealized mouth-throat model was significantly higher than in Chinese pharmacopeia throat and USP (United States pharmacopeia) mouth-throat (induction port) when tested at continuous airflow of 15 and 30 L/min. The amount of deposition under breath simulator condition was similar to that under continuous airflow of 15 L/min, but was significantly different from middle and high speed (30 and 60 L/min) of continuous airflow patterns. The inner coating on idealized mouth-throat model could increase the tiotropium bromide deposition. A new in vitro evaluation apparatus might be designed by combination of the idealized mouth-throat model and breath simulator, which might be suitable for the in vitro evaluation of inhalation solutions.
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  Preparation, Characterization and Pharmacokinetics of Lovastatin-loaded Polylactic Acid Microspheres

  RONG Xinyu1,2, WANG Yingming1, WANG Lianqing1

  2013, 44(7): 681-685.

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  The polylactic acid (PLA) microspheres loaded with lovastatin were prepared by o/w emulsionsolvent evaporation technique. The optimal microspheres had the mean particle size of (2.54±0.37)μm with a narrow size distribution, and the entrapment efficiency was (90.93±0.94)％. The observation of SEM showed that the microspheres had a spherical shape with a smooth surface. The results of FT-IR and XRPD revealed that the chemical structure of lovastatin was not changed and amorphous lovastatin might be entrapped in the microspheres. The results of in vitro release test showed that the microspheres in different batches had a good reproducibility. The pharmacokinetics in rats of the product was carried out with lovastatin tablets as the control. The results showed that cmax and tmax of lovastatin microspheres after im injection were (21.7±1.0)ng/ml and (91.5±3.0)h, while cmax and tmax of the tablets were (15.8±0.8)ng/ml and (1.7±0.1)h. Meanwhile, t1/2、AUC0→∞ and MRT of the microspheres were significantly increased. It indicated that the product could extend the retention time and improve the absorption of lovastatin in rats.
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  Effects of Gel Matrixes and Penetration Enhancers on Skin Permeability of Curcumin Liposomal Gel

  WU Qingqing1,2, YUAN Ling1,2, CHEN Yan1*, ZHANG Zhenhai1, ZHOU Lei1,2

  2013, 44(7): 686-690.

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  The effects of types and concentrations of gel matrix and the penetration enhancers on the cumulative penetration and retention amount of curcumin liposomal gel were investigated. The optimal matrix of liposomal gel was Carbomer with the concentration of 1％, and combined enhancers of 2％ Azone and 2％ menthol had the best enhancing effect. Compared with the curcumin liposomes, the liposomal gel had higher cumulative penetration amount, steady state permeation rate and skin retention, after 24 h.
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  Preparation of Capsules Filled with Simvastatin Pellets

  WEI Baokang

  2013, 44(7): 690-693.

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  Simvastatin pellets were prepared with centrifugal granulator by powder laying method with microcrystalline cellulose (MCC) as diluent and hydroxypropyl methylcellulose (HPMC) E5 solution as adhesive, then was filled into capsules. The effects of MCC amount and HPMC concentration on micromeritic properties of the pellets and yield of target pellets were investigated. The effect of diameter of bulk drug on dissolution was also investigated. The dissolution of the optimal product was similar with the commercial simvastatin capsules in four dissolution media.
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  Preparation and Anti-tumor Activity Evaluation of LyP-1-conjugated Liposomes for Tumor Targeting Drug Delivery

  WU Meilin1, WANG Fei2, HUANG Yuan1, LU Weiyue2*

  2013, 44(7): 694-701.

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  LyP-1, a cyclic nonapeptide with the function of tumor targeting, and its fluorescence labeled derivative (LyP-1-FAM) were synthesized by a solid-phase synthesis method. Functional lipid material, LyP-1-PEG 3400-DSPE, was synthesized by the specific reaction between sulfydryl and maleimide group. LyP-1-conjugated liposomes of doxorubicin (1), fluorescein (FAM) and DiR (a near-infrared fluorescent cyanine dye) were prepared by a film hydration method, respectively. The in vitro and in vivo targeting effects and anti-tumor effects on SCI 375 melanoma cells were investigated. The results showed that the in vitro cellular uptake of LyP-1-FAM or LyP-1-conjugated liposomes loaded with FAM (LyP-1-LS/FAM) was higher than 5-FAM or common liposomes of FAM (LS/FAM), respectively. After iv injection of LyP-1-conjugated liposomes of DiR (LyP-1-LS/DiR) or common liposomes of DiR (LS/DiR) to tumor bearing nude mice, the tumor fluorescence intensity of LyP-1-LS/DiR group was higher than LS/DiR group, which indicated that the targeting effect was improved after the modification of LyP-1. The IC50 values of LyP-1-conjugated liposomes of 1 (LyP-1-LS/1) and liposomes of 1 (LS/1) for SCI 375 cells were 3.4×10-6 and 8.0×10-6 mol/L, respectively. The tumor growth inhibition effect of LyP-1-LS/1 in tumor bearing nude mice was more significant than LS/1 (P<0.05).
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  Comparison of Dissolution between Self-made Amlodipine Valsartan and Hydrochlorothiazide Tablets and Exforge HCT

  HE Xiaoyan1, XIE Junxia2, HE Yuxia1, BAI Min1, CHEN Yujie1*

  2013, 44(7): 702-705.

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  The dissolution profiles of the self-made compound tablets of amlodipine, valsartan and hydrochlorothiazide were compared with the brand-name drug (Exforge HCT) in four kinds of dissolution media including pH 6.8 and pH 4.5 phosphate buffer, 0.1 mol/L HCl and water. The data were analyzed by similarity factor (f2) and difference factor (f1) methods. The results indicated that the f2 values of three components were all more than 50 and the f1 values were less than 15 in four kinds of dissolution media. It revealed that the dissolution behaviors of the selfmade tablets were similar with Exforge HCT.
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  Study on Quality of Huodan Pills

  GAO Guofeng1, ZHOU Heng2

  2013, 44(7): 705-708.

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  An UPLC method was established for the determination of taurohyodeoxycholic acid and taurochenodeoxycholic acid in Pogostemon cablin (Blanco) Benth. leaves, and a GC method was established for the determination of patchoulic alcohol. By detection of 73 batches of samples, 10 batches of Huodan pills and 18 batches of Pogostemon cablin (Blanco) Benth. leaves were unqualified.
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  HPLC Fingerprint of Ganshao Xiaoke Tablets

  HU Chunxiang1,2, ZHU Jiaxian1,2, ZHAN Changsen1,2, CHEN Zhongliang1,2

  2013, 44(7): 709-711.

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  An HPLC fingerprint spectrum method of Ganshao Xiaoke tablets was established. The samples were performed on Zorbax SB-C18 column with the mobile phase of acetonitrile-0.05％ phosphoric acid by gradient elution at the detection wavelength of 230 nm. Eight common characteristic peaks were presented in the fingerprint.
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  HPLC Fingerprints of the Prepared Medical Materials of Fructus Gardeniae

  HOU Zhifei1, LU Haigang1, WANG Gang1, XUE Na1, SUN Guoxiang2*

  2013, 44(7): 712-715.

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  The HPLC fingerprints of the prepared medical materials of Fructus Gardenia with different process were investigated. A CenturySIL C18 BDS column was used, with 1％ acetate acid-1％ acetate acid acetonitrile solution as the mobile phase by gradient elution, at the detection wavelength of 265 nm. Thirty-five co-possessing peaks were selected as the fingerprint peaks by taking geniposide peak as the reference peak. There were good similarities between the HPLC fingerprints of the prepared medical materials of Fructus Gardenia in terms of the distribution of chemical ingredients, but the quantitative similarities were not desirable. Accompanied with the intensification of the heating prepared conditions, the quantity of most ingredients showed decreased trend while a few showed increased trend.
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  Determination of Related Substances in Cefpirome Sulfate for Injection by Gradient Elution HPLC

  SHI Jieming

  2013, 44(7): 716-719.

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  A gradient elution HPLC method was established for the determination of the related substances in cefpirome sulfate for injection. A Kromasil C18 column was used with the mobile phase of phosphate buffer (pH 7.0)-acetonitrile by gradient elution at the detection wavelength of 265 nm. The results indicated that cefpirome and the related substances could be separated well. The calibration curves of cefpirome, 7-ACA and 2,3-cyclopentenopyridine (2,3-CYCPP) were linear in the concentration ranges of 1 - 16 μg/ml, 0.5 - 10 μg/ml and 1 - 10 μg/ml, respectively.
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  Progress in the Total Synthesis of Prostaglandins

  GE Yuanyuan, CAI Zhengyan, ZHOU Weicheng

  2013, 44(7): 720-728.

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  Prostaglandins are important endogenous compounds with mutiple bioactivities. There have been 14 prostaglandin analogues approved by FDA in the market for the treatment of glaucoma, ulcer, early pregnancy, constipation, hypertension etc. Recent advances in the total synthesis of prostaglandins were reviewed, including the key intermediates such as Corey lactone, cyclopentenone derivatives, bicyclic enal. The seven-step process of prostaglandin PGF2α via the intermediate bicyclic enal starting from succinaldehyde is expected to greatly reduce the production cost of related drugs.
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  Application of Computational Fluid Dynamics to Spray Drying

  YANG Jianing1, ZHAO Lijie1,2, WANG Youjie1,2, CAO Hanhan1, FENG Yi1,2*

  2013, 44(7): 729-733.

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  Computational fluid dynamics has become an important tool for study fluid flowing state and the mass and heat transfer process based on the numerical simulation, which aims at working out the equations of fluid momentum, heat and mass to obtain the thermodynamic parameters of the flowing fluid. In this paper, computational fluid dynamics technology is briefly introduced and its application to spray dryer chamber design, optimizing process parameters and reducing the wall deposition in the spray drying operation are reviewed.
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  Research on Multiple Component Facility of Intellectual Property of American

  DING Jinxi, HE Mengyun

  2013, 44(7): 734-740.

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