Chinese Journal of Pharmaceuticals

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Synthesis of Calcipotriol

WU Guangsheng, ZHANG Qingwen*

2015, 46(3): 221-224.

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(5E,7E,22E)-24-Cyclopropyl-1α,3β-bis(tert-butyldimethylsilyloxy)-9,10-secochola-5,7,10(19),22- tetraen-24-one (2) was converted to its SO2-adduct, which was subjected to stereoselective reduction with N,Ndiethylaniline- borane in the presence of chiral auxiliary (1S,2R)-(-)-cis-1-amino-2-indanol, then deprotection to give (5E,7E,22E,24S)-24-cyclopropyl-1α,3β-bis(tert-butyldimethylsilyloxy)-9,10-secochola-5,7,10(19),22-tetraen-24-ol (5). Calcipotriol was obtained via 5 deprotection of silyl groups and photoisomerization with an overall yield of 42％ based on 2.

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Synthesis of Letrozole

SUN Zhijia1, WANG Shuobing1, ZHANG Guogang2,3*

2015, 46(3): 225-226.

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Letrozole was prepared from 4-(bromomethyl)benzonitrile by reaction with sodium 1,2,4-triazol-1Hide to give 4-[(1H-1,2,4-triazol-1-yl)methyl]benzonitrile, which was subjected to reaction with 4-fluorobenzonitrile in the presence of potassium tert-butoxide with an overall yield of 54.8％.

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Synthesis of Bortezomib

ZHENG Deqiang, ZHANG Lijian, ZHANG Zhiyun

2015, 46(3): 227-229.

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Bortezomib was synthesized from methyl L-phenylalaninate hydrochloride via acylation with pyrazine-2-carboxylic acid, and hydrolysis to give (S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic acid, which was subjected to condensation with (1S,2S,3R,5S)-pinanedioxy (R)-(1-amino-3-methyl)butylboronate 2,2,2-trifluoroacetate (6), and deprotection with an overall yield of about 27％(based on 6).

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Synthesis of Acotiamide Hydrochloride Trihydrate

BAI Xiaoguang, YANG Zhiheng, LI Ziqiang, WANG Juxian, WANG Yucheng*

2015, 46(3): 230-232.

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Acotiamide hydrochloride trihydrate was synthesized from 2,4,5-trimethoxybenzoic acid by demethylation with aluminium chloride to give 2-hydroxy-4,5-dimethoxybenzoic acid, which was subjected to esterification with triphenyl phosphite and condensation with methyl 2-aminothiazole-4-carboxylate, and then acylation with N,N-diisopropylethane-1,2-diamine, salt formation and recrystalization with an overall yield of 75％.

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Synthesis of Ulipristal Acetate

LIU Qingqing, YU Yongguo, HAI Li, GUO Li, WU Yong*

2015, 46(3): 233-237.

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Ulipristal acetate was synthesized from 3,3-(ethylenedioxy)estra-5(10),9(11)-diene-17-one via acetylene addition, reaction with benzenesulfenyl chloride, debenzenesulfinyl reaction, rearrangement, carbonyl-protection to give 3,3:20,20-bis(ethylenedioxy)-17α-hydroxy-19-norpregn-5(10),9(11)-diene (7), followed by epoxidation with hexafluoroacetone as catalyst to obtain 3,3:20,20-bis(ethylenedioxy)-17α-hydroxy-5α,10α-epoxy-19-norpregn-9(11)- ene, which was subjected to Grignard addition, deprotection and acetylation with an overall yield of 23.1％ and an HPLC purity of 99.8％. The optimized process had several advantages, such as low cost, short production period and simple operations.

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A Concise Synthesis of Vadimezan

LIU Xuefeng

2015, 46(3): 238-239.

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Vadimezan was synthesized from the diazotization and bromination of 2-amino-3,4-dimethylbenzoic acid, followed by etherification with 2-hydroxyphenylacetic acid, and intramolecular Friedel-Crafts acylation in polyphosphoric acid with a total yield of 59％.

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Isolation, Purification and Structural Identification of Bacillomycin D

YAN Dazhuang1,2, XIAO Ming1, XUE Chunjia2, LU Jianguang2, FENG Jun2*

2015, 46(3): 240-244.

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Two compounds, 009 and 018, were purified by macroporous resin and reverse phase chromatography from fermentation broths of Bacillus subtilis SIPI-2014406, with purities of 99.6％. The results of antimicrobial activity assays showed that compound 009 had weak antibacterial activity, while compound 018 had inhibitory activity against Gram-negative bacteria. Amino acids composition analysis, MS, MS/MS and NMR spectrometry indicated that compound 009 was normal-C14 bacillomycin D, and compound 018 was its homologue.

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Preparation of Taurocholate Sodium from Ox Gall by Preparative HPLC

YANG Yang, ZHANG Xinxin, LIU Shengjia, ZHU Zhongliang, SUN Wenji*

2015, 46(3): 245-247.

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A preparative HPLC method was established for the preparation of taurocholate sodium from ox gall. The ox gall was soaked in 75％ ethanol and then filtered. The filtrate was adsorbed on a silica gel column, and then eluted by the lower layer of dichloromethane∶methanol∶water (70∶30∶10). The crude product of taurocholic acid was collected then separated and purified on a GRACE Adsorbosphere C18 column, with the mobile phase of methanol∶ 0.4％ sodium dihydrogen phosphate solution (55∶45), at the detection wavelength of 205 nm. The high concentration fraction of taurocholic acid was collected according to the chromatogram. After alkalization and desalination, taurocholate sodium with the purity of 98.1％ was obtained. The recovery rate was about 60％. Its structure was identified by infrared spectrum and NMR.

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Preparation and in vitro Evaluation of Arctiin Self-microemulsifying Drug Delivery System

GUAN Haiyan1, ZHAO Dehua1, LONG Jing2, LU Laichun1*

2015, 46(3): 248-253.

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Based on the analysis of solubility test and pseudoternary phase diagrams, the formulation of selfemulsifying drug delivery system (SMEDDS) loaded with arctiin (1) was further optimized by central composite design and response surface methodology with the equilibrium solubility of 1 in blank SMEDDS and particle size as indexes. The optimum formulation of 1-SMEDDS contained 1, octyl and decyl glycerate, Cremophor RH40 and Transcutol-P with the weight ratio of 4∶19∶54∶27. The content of 1 in SMEDDS was(40.09±0.06)mg/g, and the particle size of the product after microemulsion was(26.65±0.57)nm. The release behaviors of 1 from SMEDDS in different release media (pH 6.8 phosphate buffer, water and 0.1 mol/L hydrochloric acid) and using different machines (constant temperature magnetic stirrer and constant temperature bath shaker) were similar. Compared with the bulk drug, the release rate of 1-SMEDDS was accelerated in 0.1 mol/L hydrochloric acid.

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Formulation and Quality Evaluation of Aripiprazole Orodispersible Films

ZHANG Yuni1, HUANG Hua1*, ZHANG Tao2, WANG Haiyu3

2015, 46(3): 254-260.

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The aripiprazole orodispersible films were prepared by solvent casting method. The formulation influence factors (film-formers, plasticizers and fillers) were optimized by single factor test with thickness, weight, mechanical properties, disintegration time, content and content uniformity as indexes. The results showed that the optimal product with uniform thickness and good mechanical properties could rapidly disintegrate within 30 s. The weight variation, content and content uniformity also met the requirements of Chinese pharmacopoeia. The in vitro dissolution and in vivo pharmacokinetics in Beagle dogs of the optimal product were compared with the commercial aripiprazole orally disintegrating tablets (reference preparation). The results showed that the dissolution of aripiprazole orodispersible films in pH 4.0 acetate buffer was faster than that of reference preparation. The two preparations were bioequivalent in Beagle dogs.

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Preparation and Characterization of Paeonol Solid Dispersion

ZHANG Lu1, LIU Xinxiang2, YU Hong2, ZHOU Jianping1*

2015, 46(3): 261-264.

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The paeonol (1) solid dispersions with Plasdone S630 or Polyvidone (PVP) K30 as carriers were prepared by solvent evaporation method. The solid dispersions were characterized by polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetry (TGA). The results confirmed the drug was existed in an amorphous form or molecular state in the solid dispersions with 1∶3 or 1∶5 ratio
of 1 to carrier. Both Plasdone S630 and PVP K30 could increase the solubility of 1 in SGF and FaSSIF. The stability of 1-PVP K30 (1∶3) solid dispersions stored at 40 ℃ or 25 ℃ (relative humidity of 60％) for 30 d was superior to that of 1-Plasdone S630 (1∶3) solid dispersions.

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Effects of Chitosan and Its Derivatives as Coating Materials on Corneal Permeability of the Curcumin-loaded Liposomes

LI Xiang1,2, LUO Ying1, LIAO Zhenggen1, LIANG Xinli1, ZHANG Jing1*

2015, 46(3): 265-269.

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The curcumin-loaded liposomes were prepared by ethanol injection method, and the liposomes were coated with chitosan, oligochitosan, trimethyl chitosan (TMC) and carboxymethyl chitosan, respectively. The effects of chitosan and its derivatives on in vitro corneal permeability of these coated liposomes were investigated by transcorneal permeation study and confocal laser scanning microscopy (CLSM). The results showed that the TMC-coated liposomes had the strongest transcorneal permeation among these liposomes. Moreover, the fluorescence signal of TMC-coated liposomes could be detected in a distance of 60 μm below the surface of rabbit cornea. The images of CLSM showed that the TMC-coated liposomes penetrated the rabbit cornea by paracellular route. Compared with uncoated liposomes, the TMC-coated liposomes exhibited higher steady state flux and apparent permeability coefficient.

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Pharmacokinetics and Bioequivalence of Theophylline Sustained-Release Suspensions in Beagle Dogs

YANG Yang, KUANG Rongrui, TAN Qiong, XU Zhiru, QIN Yan*

2015, 46(3): 270-272.

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The bioequivalence between theophylline sustained-release suspensions (test preparation) and theophylline sustained-release tablets (reference preparation) was evaluated. A two-period crossover study was conducted. Each Beagle dog was administered a single oral dose of test or reference preparation 200 mg. An HPLC method was established for the determination of plasma concentration, and the results were calculated by noncompartmental methods. The main pharmacokinetic parameters for test and reference preparations were as follows: cmax (9.75±1.91)and(8.94± 0.86) μg/ml, tmax (2.58±0.92)and(2.67±0.82) h, AUC0→t (76.59±9.51)and (75.22±15.06) μg·ml-1·h, AUC0→∞ (79.55± 9.86)and(77.08±13.44) μg·ml-1·h, t1/2 (3.19±0.95)and(3.18±0.63) h, MRT (5.80±0.55) and (6.08±0.83) h. The statistical analysis of the results showed that the two preparations were bioequivalent.

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Determination of Felodipine by LC-MS/MS in Human Plasma and Its Pharmacokinetics

CAI Hualin1,2,3, DENG Yang1,2,3, LI Huande1,2, PENG Wenxing1,2*, ZHU Ronghua1,2

2015, 46(3): 273-276.

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A LC-MS/MS method was established for the determination of felodipine in human plasma. Nefidipine was used as the internal standard, with the application of a Phenyl-hexyl column, in multiple reaction monitoring mode under electrospray ionization condition. It was linear in the range of 0.05 - 40 ng/ml. The extraction recoveries were 71.8％ - 77.4％, with the intra- and inter-day RSDs less than 6.3％. An oral dose of elodipine sustainedrelease tablet 10 mg (test or reference preparation) was administrated to 20 healthy male volunteers according to an open randomized crossover design. The main pharmacokinetic parameters were as follows: cmax (4.259±2.342) and (3.971± 1.767) ng/ml, tmax (4.4±2.3) and (4.0±2.0) h, t1/2 (13.2±3.4) and (12.4±2.5) h, AUC0→48 h (43.647±15.158) and (42.448± 14.744) ng·ml-1·h, AUC0→∞ (47.085±16.695) and (45.503±15.828) ng·ml-1·h.

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Determination of Related Substances in Paclitaxel by HPLC

SHEN Weiyang1, SHI Wenli1, SHEN Puyi2, SHI Rui2, JIN Xiangfei1

2015, 46(3): 277-281.

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An HPLC method was established for the determination of 14 known related substances of paclitaxel, including their correction factors. A C18 column was used with the mobile phase of acetonitrile∶water by gradient elution, at the detection wavelength of 227 nm. The related substances were completely separated from the main constituent. The calibration curves were linear for 14 known related substances in their corresponding concentration ranges. Their average recoveries were 96.8％ - 113.4％, with RSDs of 1.3％ - 6.4％.

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Comparation on the Qualities of Poria, Ramulus Cinnamomi, Rhizoma Atractylodis macrocephalae and Radix et Rhizoma Glycyrrhizae Dispensing Granules

HAO Yunfang, NI Yan, CHENG Yuchuan, LI Xianrong*

2015, 46(3): 282-286.

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The qualities of Poria, Ramulus Cinnamomi, Rhizoma Atractylodis macrocephalae and Radix et Rhizoma Glycyrrhizae dispensing granules from different manufactures were compared. The comparative investigation on different dispensing granules was made mainly through appearance, solubility, labeling specification, determination and fingerprint. The results showed that the dispensing granules were quite different from appearance, contents of active
ingredient and fingerprints. It suggested that the unitary quality criterion was a necessitated problem at present.

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Determination of Gallic Acid in Propyl Gallate Injection by HPLC

CHEN Hong

2015, 46(3): 287-289.

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An HPLC method was established for the determination of the related substance (gallic acid) in propyl gallate injection. A C18 column was used with the mobile phase of methanol∶water (adjusted to pH 3 with phosphoric acid) by gradient elution at the detection wavelength of 272 nm. The results indicated that propyl gallate and gallic acid could be separated well. It was linear for gallic acid in the range of 0.125 - 5.0 μg/ml. The low limit of detection was 7.5 ng/ml. The average recovery of gallic acid was 100.1％, with RSD of 0.31％.

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Preparation and Application of Levofloxacin Hydrochloride Electrode Based on Film of Molecularly Imprinted Polymer

WANG Shengjuan, WANG Yuan, CHENG Pengyu, WANG Jing, XIU Rong*

2015, 46(3): 290-292.

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With levofloxacin hydrochloride as the templet, and o-phenylenediamine and m-dihydroxybenzene as the functional monomer, a molecularly imprinted polymer membrane sensor of levofloxacin hydrochloride was prepared on the surface of a glassy carbon electrode by using cyclic voltammetry (CV) electropolymerization method. Electrochemical behavior of the sensor was characterized by CV and differential pulse voltammetry (DPV). The peak
currents of DPV and concentration had a good linear relationship in the range of 1.0×10-9 - 3.8×10-7 mol/L, with a detection limit of 8.2×10-10 mol/L.

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Delamination Propensity of Pharmaceutical Glass Containers Treated with Different Extraction Media by Accelerated Testing

LI Ye, ZHANG Yilan*

2015, 46(3): 293-298.

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Different extraction media [0.9％ KCl solution with or without edetate (EDTA)] were added into pharmaceutical glass containers provided by two manufacturers. After sterilization (121 ℃, 1 h) and accelerated test (stored at 60 ℃ for 30 d), the effect of media on delamination propensity of pharmaceutical glass containers was investigated with the results of visual inspection, particle analysis, determination of Si ion concentration and scanning lectron microscopy as indexes. Meanwhile, the hydrolytic resistance test of inner surface according to US pharmacopoeia USP) was also performed to investigate whether there was a correlation between the results of hydrolytic resistance etermined with the USP method and evidence of delamination. The results showed that the EDTA-containing medium aused different degrees of erosion of inner surface of vials provided by two manufacturers. The results of hydrolytic
resistance test could not be used as indicators of the chemical durability of the glass containers.

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Research Progress of Impurity Profiles in Macrolide Antibiotics

HUANG Shan1, LI Yue1*, ZHU Hongji2

2015, 46(3): 299-304.

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Controlling impurities in drugs is important to ensure drug safety. Macrolide antibiotic is one of the most widely used antibiotics in clinical, which are mainly produced by fermentation and then modified by chemical derivation. Macrolide antibiotics are consist of various components. Their related substances are multipled and diverse. The impurities should be controlled, which is crucial for the effective control of the product quality. With the rapid development of modern instruments and analysis techniques, many sensitive methods for impurity profiles are provided. This article reviews the sources and classifications of related substances in macrolide antibiotics, as well as the establishment of impurity profiles.

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Research Progress in Curcuminoids and Biological Activity

LI Ziqiang, BAI Xiaoguang, YANG Zhiheng, WANG Yucheng*

2015, 46(3): 305-311.

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In this paper, the research progress of curcuminoids in recent years is reviewed. The curcuminoid derivatives were summarized and classified according to their different structures. The relationships of their structures and antioxidant, anticancer, anti-inflammatory, HIV inhibition, and antimicrobial activity were summarized to provide references for further studies.

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Scheduling of Double-bath Automatic Dissolution System with On-line Dilution and Testing

LIU Qian1, SONG Dongmei1, CHEN Yang1, YANG Yongjian1*, SHI Lifang2

2015, 46(3): 312-315.

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A double-bath automatic dissolution system with on-line dilution and testing was built. The time scheduling to coordinate the double baths, double collection pumps, double loss replacement subsystems, dilution workstation, UV injection subsystem and UV detection was studied to make sure the time points of sampling, dilution and injection were controlled precisely. The scheduling was optimized to improve the efficiency and avoid the conflicts among the collection, the sample dilution and measurement time. The system was validated by the ambroxol hydrochloride test, which collected 60 samples at 5 time points in 30 min, and coordinated the dilution, injection and measurement procedures automatically. The results showed that the efficiency could be improved by more than 100％ while the result was promised with well-designed time scheduling.

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Graphical Synthetic Routes of Tedizolid Phosphate

WANG Jiahui, ZHAO Chuanmeng, ZHANG Fuli*

2015, 46(3): 316-318.

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The Analysis of Pharmaceutical R&D Collaboration Models with Virtual Pharmaceutical Companies as Major Player

WANG Hong, FENG Guozhong*

2015, 46(3): 319-323.

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