Chinese Journal of Pharmaceuticals

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Synthesis of Vildagliptin

SONG Wei-Guo1,2, FU Yong-Qiang2, ZHANG Xiao-Pan2, XIA Yan2, XU Wen-Fang1*

2012, 43(12): 965-967.

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Vildagliptin, an antidiabetic drug, was synthesized from L-prolinamide, chloroacetyl chloride and trifluoroacetic anhydride to give (S)-N-chloroacetyl-2-cyanopyrrolidine, which was followed by reaction with 3-amino-1-adamantanol with an overall yield of about 70％(based on L-prolinamide).

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Synthesis of Related Substances of Ziprasidone

SUI Qiang, TANG Chao, LIU Shuai, WANG Xiao-Mei, SHI Hui-Lin

2012, 43(12): 971-973.

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To perform the quality control of antipsychotic drug ziprasidone, four related substances recorded in USP 35(2012) were prepared, and their structures were confirmed by 1 H NMR and MS. These substances were 2-[2-amino-5-[2-[4-(benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl]-4-chlorophenyl]acetic acid(2), 5-[2-[4-(benzo[d]- isothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloroindoline-2,3-dione(3), 5,5′-bis[2-[4-(benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl]-6,6′-dichloro-3-hydroxy-3,3′-biindoline-2,2′-dione(4) and 3-(benzo[d]isothiazol-3-yl)-5-[2-[4-(benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloroindolin-2-one(5).

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PU Tong, WANG Nai-Xing, FAN Yi, CHEN Tian

2012, 43(12): 974-976.

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To perform the quality control of antiviral agent valaciclovir hydrochloride, two related substances recorded in EP 7.0, N-methylvalaciclovir and N-ethylvalaciclovir, were synthesized from N-Cbzvalaciclovir by N-alkylation with methyliodide and ethyliodide respectively to give N-Cbz-N-methylvalaciclovir or N-Cbz-Nethylvalaciclovir,which were subjected to deprotection catalyzed by Pd/C. It is an improved method for the N-alkylation of sterically hindered N-Cbzamino acid derivatives.

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Synthesis of 4-(3-Pyridyl)-1H-imidazole

CAO Zhi-Ling1,2, LIU Bing2, LIU Wen-Jie1, SONG Xiao-Kai1, BAO Wen-Ming1

2012, 43(12): 976-977.

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4-(3-Pyridyl)-1H-imidazole, the intermediate of telithromycin, was synthesized from 3-(α-bromoacetyl)pyridine by oxidation with DMSO to give pyridylglyoxal, followed by Debus-Radziszewski cyclization with ammonium acetate and formaldehyde with an overall yield of about 66％.

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Bioreduction of 3,5-Bis(trifluoromethyl)acetophenone by Resting Cells of Saccharomyces rhodotorula in Cloud Point System

ZHANG Fang1,2, WANG Min3*, LI Li3, QIN Jing-Yi3

2012, 43(12): 978-982.

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The aromatic ketone 3,5-bis(trifluoromethyl)acetophenone was bioreducted by resting cells of Saccharomyces rhodotorula in cloud point system (CPS) composed of two surfactants with different cloud points. The effects of the CPS on cell growth and substrate conversion were studied respectively. Triton X-114 (TX-114) could significantly enhance the tolerance to the toxic substrate in cell growth period. The product concentration and conversion rate in bioconversion with 5％ surfactant and 6 μl/ml substrate were 5.47 mg/ml and 80.5％, respectively, enhanced by 91.3％ and 78.1％ comparaed with the two-phase system. The activity of the resting cells remained over 80％ after 4 times of periodic duty.

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Separation, Fraction and Process Characteristics of Gelatin Peptides with Specific Molecular Weight Distribution

LIU Tao1,2.3, JIN Xiao-Bao1, YIN Hui1, LI Ming3, ZHU Jia-Yong1*

2012, 43(12): 983-986.

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The preparation of gelatin peptides with specific molecular weight distribution had attracted wide attentions for higher value application of officinal gelatin and collagen. However, the separation of gelatins with specific molecular weight distribution was difficult because of its dispersity and inhomogeneity. In this study, gelatin materials with Mn 4.5×104 were separated and fractioned by thermal degradation, ultra filtration and organic solvent precipitation to obtain gelatins with Mn 2.5×104 - 3.5×104. The gelatin peptides with Mn 2.8×104 were prepared successfully and the molecular distribution closed to normal distribution. The retention behavior, membrane separation characteristics and fraction ways were also discussed.

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Chemical Constituents in Chloroform Fraction of Abelmoschus esculentus

SHI Jin-Min1, LI Zhen2, JING Lin-Lin1, ZHONG Li-Jun1, JIA Lu1*

2012, 43(12): 987-990.

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MCI, ODS and silica gel column chromatography were used to investigate the chemical constituents of the chlorform fraction of Abelmoschus esculentus. On the basis of spectral data and physicochemical properties, twelve compounds were isolated and identified as quercetin(1), stigmast-5-ene-3β,7α-diol(2), ursolic acid(3), dammar-24-ene-3β-acetoxy-20-ol(4), dammarane-3β,25-diol-20,24-epoxy-3-acetate(5), α-monpalmitin(6), cleomiscosin A(7),cleomiscosin C(8), isobauerenyl acetate(9), scopoletin(10), syringaresinol (11) and liriodendrin(12). Except of 1, the other compounds were reported from A. esculentus for the first time.

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Preparation of Magnolol Loaded Polyethylene Glycol-poly(L-Lactic Acid) Electrospun Fibers and Drug Release by Enzyme Degradation

WANG Hao1, DENG Ying-Jie2

2012, 43(12): 991-997.

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Magnolol loaded fiber mats were prepared by high-voltage static electrospinning with polyethylene glycol-poly(L-lactic acid) as carrier. The observation of scanning electron microscope and the measurement results of the Photoshop 5.0 showed that the surface of the electrospun fiber was smooth and the diameter of fiber was homogeneous.The results of wide-angle X-ray diffraction test showed that there was no crystalline state on fibrous surface. The release
behaviors of magnolol from the fiber mats in phosphate buffer with or without proteinase K were determined by HPLC.The results showed that the release rate was significantly increased in the proteinase K containing medium, even the enzyme concentration was 2.5 μg/ml. The release rate of magnolol continuously rose with the increasing of enzyme concentration (from 2.5 μg/ml to 10 μg/ml), but the rate was smaller. The release curves of the samples in enzyme free medium were divided into several sections to fit Higuchi equation well, while the drug release behavior before the platform in the enzyme-containing medium fit the first order equation well.

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Preparation of Fluoxetine Hydrochloride Enteric Tablets

FAN Xin-Hua, TU Yong-Rui

2012, 43(12): 998-1002.

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The formulations of tablet core, isolating layer and enteric layer coating solution for fluoxetine hydrochloride enteric tablets were optimized by single factor test. The results showed that the amount of three key excipients (hydroxypropyl methyl cellulose E50, sodium carboxymethyl starch and microcrystalline cellulose) in the tablet core were 5％, 15％ and 25％, respectively. The adhesive for tablet core was 5％ starch slurry. The isolating layer was coated by 5％ Opadry Y-1-7000 aqueous dispersion with the coating level of 1％. Then the enteric layer was coated by 5％ polyacrylic resin L30-55 (containing 5％ glycerin monostearate and 1％ mannitol) with the level of 3％. The cumulative release at 2 h of the product in 0.1 mol/L HCl was less than or equal to 5％, while the drug could completely release in the pH 6.8 buffer within 30 min. The in vitro release curves of three batches of the product were all similar to the reference preparation (Prozac Weekly capsules). The similarity factors (f2) between three batches of the product and reference capsules were all over 50.

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Preparation of Aprepitant Emulsion for Intravenous Injection

ZHOU Wei, CHEN Fei, CHEN Ning, MAO Ke

2012, 43(12): 1003-1006.

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The formulation of aprepitant emulsion for intravenous injection was optimized by single factor test and orthogonal design. The properties, such as appearance, particle size, ζ potential and stability of the product were investigated. The results showed that the type and amount of emulsifier as well as the amount of oleic acid had the greater effect on stability. The optimal formulation of aprepitant emulsion was as follows: aprepitant was 0.25％, soybean oil was 15％, egg yolk lecithin E80 was 2.5％ and oleic acid was 0.125％. The appearance of the product was ivory. The average particle size, PDI, centrifugal stability constant (Ke), ζ potential, pH value and drug content of the product before and after sterilization were (218.71±1.26) and (220.3±0.53)nm, 0.203±0.016 and 0.210±0.009, 0.21±0.01 and 0.34±0.01,(-37.8±0.2) and (-37.6±0.8)mV, 7.21±0.23 and 7.31±0.30, (101.03±0.89)％ and (101.12±1.20)％, respectively.

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Preparation of Multiple-unit, Pulsatile Controlled-release Orally Disintegrating Tablets. Ⅲ. Release Mechanism and Preliminary in vivo Evaluation of Orally Disintegrating Tablets Containing Diltiazem Hydrochloride Pulsatile Controlled-release Pellets

LIANG Chao-Feng1, ZHOU Tao1, CHEN Tong-Kai1, ZHENG Ying-Yan1, ZHONG Guo-Ping2

2012, 43(12): 1007-1011.

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The in vitro release curves of three batches of orally disintegrating tablets containing diltiazem hydrochloride pulsatile controlled-release pellets were drawn and different mathematical models were applied to fit above data so that the release mechanism was investigated. The results showed that the cumulative release during the first 4 h was below 10％, the zero model and Higuchi model fit well with the release data during 0 - 24 h and 5 - 24 h, respectively. The pharmacokinetics of the orally disintegrating tablets in six health volunteers was investigated with the commercial controlled-release capsules (Herbesser) as the reference. The results showed that the product with the lag time of 4 -5 h had an expected pulsatile and controlled release effect compared with reference preparation. The Loo-Riegelman method was used to calculate the in vivo absorption percentage, and linear regression was made with in vitro release data of corresponding time. The correlation coefficient was 0.997 0 of the regression equation. It revealed that there was a significant correlation between in vitro release and in vivo absorption.

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Isolation and Structure Identification of Related Substances from Cholic Acid

JIANG Meng-Hong1, SHEN Wen-Bin2, YUAN Kai-Kai3, SU Meng-Xiang1, DI Bin1*

2012, 43(12): 1012-1015.

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Cholic acid is the primary bile acid that is made from bile and bile extract of animal by saponification,acidification and purification, which may be widely used to make some compound preparations such as artificial bezoar,Qingkailing oral liquid and Qingkailing injection. The structures of the two unknown related substances isolated from cholic acid were determined by NMR spectrum including 1H NMR, 13C NMR, DEPT, 1H-1H COSY, HSQC, HMBC and
high resolution mass spectrometry. They were identified as 3α,12α-dihydroxy-7-oxo-5β-cholan-24-oic acid and 3α,7α-dihydroxy-12-oxo-5β-cholan-24-oic acid. Their data of 1H NMR and 13C NMR were assigned.

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Determination of Quercetin, Kaempferol, Isorhamnetin and Their Total Flavonol Glycosides in Ginkgo Biloba Extract Injection by HPLC

LIN Jia-Yuan, ZHANG Peng, CAI Wei-Min, MA Guo*

2012, 43(12): 1016-1019.

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An HPLC method was established for the determination of quercetin, kaempferol, isorhamnetin and their total flavonol glycosides in Ginkgo Biloba extract injection and the quality evaluation of two brands. A Diamonsil C18 column was used with the mobile phase of methanol-0.4％ phosphoric acid (55︰45) at the detection wavelength of 360 nm. Quercetin, kaempferol and isorhamnetin in the unhydrolyzed and hydrolyzed Ginkgo Biloba extract injection showed good separation and linearity ranges. The average recoveries of quercetin, kaempferol and isorhamnetin in the unhydrolyzed and hydrolyzed samples were 100.2％, 100.3％, 100.2％ with RSDs of 0.64％, 1.14％, 0.40％, and 100.0％,100.7％, 100.3％ with RSDs of 0.79％, 0.98％, 1.00％, respectively.

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Quality Standard for Composite Salvia miltiorrhiza Capsules

XU Yong, ZHU Yan-Rong, WANG Ke, JI Shen*

2012, 43(12): 1020-1023.

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The Radix Notoginseng and Radix Salvia miltiorrhizae in composite Salvia miltiorrhiza capsules were identified by TLC and the salvianolic acid B was determined by HPLC. In the identification test of Radix Notoginseng,the impurities of the sample was removed by solid phase extraction column with water and 30％ methanol to reduce the interference on determination, then the sample was eluted with methanol. The eluent was detected by TLC with
dichloromethane-ethanol-water (70∶45∶6.5) as the developer. The results showed that the notoginsenoside R1,ginsenoside Re, Rb1 and Rg1 in Radix Notoginseng could achieve an effective separation. The content of salvianolic acid B was determined by HPLC. A C18 column was used with the mobile phase of methanol-acetonitrile-formic acid-water (30∶10∶1∶59). The detection wavelength was 286 nm. The calibration curve of salvianolic acid B was linear in the range of 0.1 - 10 μg. The established qualitative and quantitative methods were simple, accurate and specific, and they could effectively control the quality of composite Salvia miltiorrhiza capsules.

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The Related Substances of Ampiroxicam

ZHANG Pei-Long1, YU Fang1, WANG Ying2, DU Ji-Hang1

2012, 43(12): 1024-1026.

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The impurities in the ampiroxicam (1) synthesis process were separated and purified. The structure of one compound was confirmed by LC-MS and 1H NMR to be 6-methyl-6H-7-oxopyrido[1,2-a]pyrimido[5,4-c]-1,2-benzothiazine-5,5-dioxide (3). An HPLC method was established for the determination of the related substances in 1. An ODS column was used with the mobile phase of 0.05 mol/L potassium dihydrogen phosphate buffer solution (adjusted to pH 4.5 with phosphoric acid)-acetonitrile by gradient elution at the detection wavelength of 314 nm. The calibration curves of the related substances including piroxicam (2) and 3 were linear in the concentration range of 0.3 - 1 μg/ml.Their average recoveries were 105.0％ and 100.8 ％, with RSDs of 1.19％ and 0.91％.

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Determination of Notoginsenoside R1, Ginsenoside Rg1, Ginsenoside Re and Ginsenoside Rb1 in Fufang Danshen Tablets by HPLC

LU Ji-Wei, YU Jian, WANG Ke, JI Shen*

2012, 43(12): 1027-1030.

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An HPLC method was established for the determination of notoginsenoside R1, ginsenoside Rg1,ginsenoside Re and ginsenoside Rb1 in Fufang Danshen tablets. A Kromasil C18 column was used with the mobile phase of acetonitrile-water by gradient elution at the detection wavelength of 203 nm. Their calibration curves were linear in a relatively wide concentration range. The recoveries were 96.0％ - 101.8％, with RSDs less than 1.8％.

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GC Fingerprint of Volatile Components in Xingnaojing Fat Emulsion Injection

ZHANG Lai-Fang, YU Hai-Rong, ZHANG Xi-Quan

2012, 43(12): 1031-1034.

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GC fingerprint of volatile components in Xingnaojing fat emulsion injection was established. A DB-1 capillary column was used, and the temperature of injection port and detector (FID) were set at 180 ℃ and 250 ℃,respectively. The initial column temperature was set at 50 ℃ and elevated to 150 ℃ at the rate of 6 ℃/min and maintained at 150 ℃ for 11 min, then it was further increased to 220 ℃ at the rate of 6 ℃/min and kept at 220 ℃ for 20 min.Nitrogen was used as the carrier gas at a flow rate of 1.5 ml/min with a split ratio of 10︰1. Eleven common peaks were identified from GC spectrum of 10 batches of self-made Xingnaojing fat emulsion injection. The peak of borneol which was the main active component in Borneolum syntheticum was selected as the standard peak. The reproducibility of this method was good, and the separation of the common peaks was satisfactory.

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Determination of Eight Residual Organic Solvents in Docetaxel by Headspace Capillary Gas Chromatography

YE Xiao-Xia1,2, YANG Yong-Jian2*, JIN Fang1

2012, 43(12): 1035-1036.

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A headspace capillary gas chromatography method was established for the determination of methanol,acetone, dichlormethane, hexane, ethyl acetate, tetrahydrofuran, heptane and pyridine in docetaxel. A DB-624 capillary column was used with the application of FID detector. The recoveries of the above organic solvents were 99.3％ - 103.5％, with RSDs less than 2.4％.

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Progress in Thermoplastic Elastomer Pressure Sensitive Adhesive for Transdermal Drug Delivery System

MA Jian-Fang, LUO Hua-Fei, ZHU Zhuang-Zhi, CHEN Chun, WANG Hao*

2012, 43(12): 1037-1042.

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Thermoplastic elastomer (TPE) is a kind of triblock copolymer with the characteristics of high elasticity at room temperature and plasticity at high temperature. It can be used for the preparation of hot melt pressure sensitive adhesive (HMPSA) and solvent pressure sensitive adhesive (PSA). The matrix formulation, final product type and indexes of quality evaluation are reviewed in this paper. The gap between domestic and foreign TPE-PSA is briefly discussed.

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Graphical Synthetic Routes of Saxagliptin

ZHAO Hao-Yu1, XIE Ting2

2012, 43(12): 1043-1046.

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Graphical Synthetic Routes of Rivaroxaban

LI Chao1, GUO Jin-Cai1, ZHANG Yong-Jun2, ZHANG Xing-Xian1*

2012, 43(12): 1046-1048.

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