Chinese Journal of Pharmaceuticals

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Synthesis of Retapamulin

HUANG Huoming, HAO Qun*, LI Hongyan, ZHOU Weicheng

2014, 45(12): 1101-1103.

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Retapamulin was prepared in a total yield of 45.9％ by nucleophilic substitution of endo-8-methyl-8-azabicyclo[3.2.1]octan-3-yl methanesulfonate and sodium N,N-diethyldithiocarbamate trihydrate to give exo-8-methyl-8-azabicyclo[3.2.1]octan-3-yl N,N-diethyldithiocarbamate, followed by hydrolysis and condensation with pleuromutilin-22-mesylate.

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Synthesis of Axitinib

FANG Zheng1, MA Xiangjun2, XU Jiafeng2, WEI Ping2, GUO Kai2*

2014, 45(12): 1104-1107.

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Axitinib was synthesized from 2-methyl-5-nitro-aniline by cyclization, iodination, protection with DHP, Heck coupling reaction and reduction to give (E)-6-amino-3-[2-(pyridin-2-yl)vinyl]-1-(tetrahydropyran-2-yl)-1H-indazole, which was subjected to diazotization and reaction with 2-mercapto-N-methylbenzamide to afford (E)-Nmethyl-2-[[3-[2-(pyridin-2-yl)vinyl]-1-(tetrahydropyran-2-yl)-1H-indazol-6-yl]sulfanyl]benzamide, followed by deprotection with 4-methylbenzenesulfonic acid with an overall yield of about 23.2％.

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ZHU Meiyu, ZHENG Yongyong, ZHOU Yimeng, ZHOU Feng, LI Jianqi*

2014, 45(12): 1108-1112.

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Four related substances of dabigatran etexilate were synthesized, and their structures were confirmed by 1H NMR, MS and 13C NMR. They were 3-[2-[[(4-carbamimidoylphenyl)amino]methyl]-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido]propanoic acid (1), 3-[2-[[[4-[N'-[(hexyloxy)carbonyl]carbamimidoyl]phenyl]amino]methyl]-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido]propanoic acid (2), ethyl 2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzo[d]imidazole-5-carboxylate (3) and ethyl 2-[[(4-carbamimidoylphenyl)amino]methyl]-1-methyl-1H-benzo[d]imidazole-5-carboxylate
4-methylbenzene sulfonate(4).

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XUE Chenchen, PEI Shuchen, XU Tao, HAI Li, WU Yong*

2014, 45(12): 1112-1116.

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According to the synthetic process of bazedoxifene and the source of related substances, five related substances of bazedoxifene acetate, a selective estrogen receptor modulator were synthesized and confirmed by 1H NMR, 13C NMR and MS. They were 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol(6), 1-[4-[2-(azepan-1-yl)ethoxy]benzyl]-5-benzyloxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole(7), 3-[4-[2-(azepan-1-yl)ethoxy]benzyl]-2-(4-hydroxyphenyl)-3-methyl-3H-indol-5-ol(8), 1-(4-hydroxybenzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol(9), and 1-[4-[2-(azepan-1-yl)ethoxy]benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol-N-oxide(10). These substances were taken as the references for the quality control of bazedoxifene.

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SU Guoqiang1, LIU Shihui2, CHEN Shaohua2, HU Yanwei2, ZHANG Shilei2*

2014, 45(12): 1117-1120.

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To perform the quality control of duloxetine hydrochloride, the related substance 2-[3-(methylamino)-1-(thiophen-2-yl)propyl]naphthalen-1-ol(related substance E) recorded in EP 7.5 was prepared from 2-thenaldehyde and triethyl phosphonoacetate via Horner-Wadsworth-Emmons reaction, reduction with diisobutyl aluminium hydride, oxidation, Friedel-Crafts reaction and reductive amination with methylamine/sodium borohydride.The structure was confirmed by 1H NMR, 13C NMR and HRMS.

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Synthesis of 6-Fluoro-3,4-dihydro-2-(oxirane-2-yl)-2H-chromene

SHEN Zheng, GE Jilong*, TU Yongrui, WANG Yan, DONG Xiuzhong

2014, 45(12): 1120-1122.

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6-Fluoro-3,4-dihydro-2-(oxirane-2-yl)-2H-chromene, the key intermediate of nebivolol, was synthesized from 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylic acid via esterification, Ylide reaction, halogenation,reduction and cycloaddition with an overall yield of 70％.

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Synthesis of 3'-Amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic Acid

XU Hao, WU Xuesong, CEN Junda*

2014, 45(12): 1123-1124.

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6-Bromo-2-nitrophenol was subjected to benzyl protection to give 2-benzyloxy-l-bromo-3-nitrobenzene, which was further treated with 3-carboxyphenylboronic acid to afford 2'-benzyloxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid via Suzuki coupling reaction. Subsequent hydrogenation with Pd/C catalysis provided the desired 3'-amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid which was an key intermediate in the synthesis of eltrombopag with an overall yield of 71％.

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Stereoselectivity Synthesis of (1R,2R)-2-(3,4-Difluorophenyl)cyclopropanecarboxylic Acid

MA Qingwen, WANG Zengxue*

2014, 45(12): 1125-1127.

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(1R,2R)-2-(3,4-Difluorophenyl)cyclopropanecarboxylic acid was synthesized by condensation of 3,4-difluorobenzaldehyde with malonic acid to give (E)-3-(3,4-difluorophenyl)acrylic acid, followed by reduction and Simmons-Smith asymmetric cyclopropanation to give [(1R,2R)-2-(3,4-difluorophenyl)cyclopropyl]methanol, which was subjected to oxidation in the present of periodic acid and chromium trioxide with an overall yield over 80％ (based on 3,4-difluorobenzaldehyde).

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Degradation of Residual Tylosin in Waste Water

CHEN Xuejun, TAO Haiming, LI Zhenwu, MIAO Jianyu, XIONG Zhengjun*

2014, 45(12): 1135-1138.

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The degradation effects of the residual tylosin in waste water by acid, alkali and oxidant were investigated. It was concluded that the degradation of tylosin was obvious with adding 2.5％ sodium hydroxide at 60 ℃ or 0.5％ sodium hypochlorite at 25 ℃ into waste water, and the residual content of tylosin in the waste water could meet the requirements of limitation, which could be discharged after treating by activated sludge. However, the effect of acid treatment was poor. With the consideration of production cost and EHS requirements, the alkali treatment method could be used in the practical production.

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Preparation and Pharmacokinetics in Rats of Topotecan Hydrochloride Liposomes by Ammonium Sulfate Gradient Method

XU Leilei1, CHEN Xianzhi2, LI Yaping1,3, GU Wangwen3*

2014, 45(12): 1139-1142.

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The topotecan hydrochloride liposomes modified with distearoyl phosphatidyl ethanolaminepolyethylene glycol (DSPE-PEG) were prepared by ammonium sulfate gradient method with hydrogenated phospholipids and cholesterol as lipid materials. The effects of formulation factors on encapsulation efficiency of the product were investigated by single factor tests. The differences of in vitro release and in vivo pharmacokinetics in rats between the optimal product and common injection were compared. The results showed that the encapsulation efficiency of the optimal product was (93.14±1.52)％ with the mean particle size of 69.6 nm. The drug could completely release within 144 h in the medium containing 10％ fetal bovine serum. Furthermore, the AUC0→t of the liposomes group was 61 times higher than that of the injection group.

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Preparation of Moxifloxacin Hydrochloride Ion-temperature Sensitive in situ Ophthalmic Gel

XU Ying, ZHANG Yan*

2014, 45(12): 1143-1146.

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The in situ gel loaded with moxifloxacin hydrochloride for ophthalmic use was prepared with Poloxamer 407 and Poloxamer 188 as temperature sensitive matrices and sodium alginate and hypromellose (HPMC) E50LV as ion sensitive matrices. The formulation was optimized with gelation temperature, gelation time, viscosity and drug release as indexes. The results showed that the optimal composition of the gel base was 0.5％ of sodium alginate,
0.3％ of HPMC E50LV, 5.9％ of Poloxamer 188 and 17.7％ of Poloxamer 407. The product was freely flowing liquid at room temperature and it converted to a film gel at 33 ℃ after diluted by simulated tear fluid. The in vitro release of moxifloxacin hydrochloride from the in situ gel was completed within 4 h.

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Preparation of Curcumin Hydroxypropyl-β-cyclodextrin Inclusion Complexes with Supercritical CO2

ZHANG Zhiyun, ZHANG Wei, WANG Lihong, LI Tong, ZHOU Lili*

2014, 45(12): 1147-1150.

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To improve the solubility of curcumin, the hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complexes of curcumin were prepared with supercritical CO2. The process parameters were optimized with single factor test and Box-Behnken surface response design with solubility of curcumin as the index. The obtained optimal process was as follows: the inclusion complexes in 0.96∶1 molar ratios of curcumin to HP-β-CD were prepared at 57 ℃ for 2 h under the pressure of 24 MPa. The solubility of the curcumin-HP-β-CD inclusion was 34.24 μg/ml, which was about 400 times higher than that of the bulk drug. The results of DSC analysis confirmed the formation of the inclusion complexes between curcumin and HP-β-CD.

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Preparation and Quality Evaluation of o/w Gel Loaded with Econazole Nitrate and Triamcinolone Acetonide

LI Jingyi, HUANG Hua*

2014, 45(12): 1151-1154.

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The formulation of oil-in-water gel loaded with econazole nitrate (1) and triamcinolone acetonide (2) were optimized by orthogonal design with appearance, centrifugal stability, viscosity, flowability, pH value and drug crystal precipitation as indexes. The optimal formulation was as follows: the amounts of 1,2-propylene glycol, 95％ ethanol and carbomer were 30％, 18％ and 1.5％, and the ratio of oil phase to aqueous phase was 25∶75. The mean contents of 1 and 2, viscosity and pH value of the optimal product were (100.1±0.3)％,(99.9±0.5)％, (37.8±0.6)Pa·s and 5.3±0.3, respectively. The transdermal behaviors of the self-made product and commercial cream (Pevisone) were investigated with excised pig skin as a barrier. The results showed that the transdermal behavior of 1 in the above two preparations had no significant difference. The results of preliminary stability test showed that the appearance, pH value,
drug contents of the product stored at 30 ℃ and 65％ relative humidity for 6 months had no significant changes.

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Preparation of Mycophenolate Mofetil Pellets by Extrusion-spheronization Process

LIU Zhihong1, ZHANG Jing1, CHEN Ting1,2, SONG Hongtao1, ZHANG Qian3*

2014, 45(12): 1155-1159.

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The mycophenolate mofetil (1) pellets were prepared by extrusion-spheronization method. The process parameters of extrusion-spheronization and formulation factors such as the amounts of adhesive, disintegrant and microcrystalline cellulose were optimized by single factor test. The optimal formulation contained 75％ of 1, 15％ of microcrystalline cellulose, 10％ of carboxymethylstarch sodium as disintegrant with 25％ ethanol containing 1.5％ of
carmellose sodium as adhesive. The rates of extrusion and spheronization were 928 r/min, the time of spheronization was 5 min. The pellets prepared under above conditions were smooth, hard and round enough to be coated in the following step. Furthermore, in pH 6.8 sodium phosphate buffer containing 0.5％ sodium dodecyl sulfonate, the cumulative release at 2 h of the optimal pellets was above 80％.

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Safety Evaluation of Huperzine A Microemulsion for Nasal Delivery on Toad Palate Cilia and Rat Nasal Mucosa Cilia

ZHANG Wanggang1, ZHENG Gaoli2, Lü Liangzhong1, WANG Shenghao2, CHEN Guoshen2*

2014, 45(12): 1160-1162.

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The effects of huperzine A (1) microemulsion for nasal delivery on survival time and transporting ability of cilia were evaluated with in situ toad palate model. Meanwhile, the appearance of rat nasal mucosa cilia treated with 1 microemulsion was observed by scanning electron microscope (SEM). Compared with the saline group, the survival time of cilia on toad palate treated by 1 microemulsion had no significant differences (P>0.05). The transporting
ability of cilia on toad palate before and after administration had no obvious changes (P>0.05). The observations of SEM analysis showed that the appearance of rat nasal mucosa cilia perfused with 1 microemulsion for 2 h had no obvious changes, but had a slight change after perfusion for 4 h. It indicated that the 1 microemulsion for nasal delivery had a minor irritation to the nasal mucosa cilia.

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Determination of Rivaroxaban in Beagle Dog Plasma by LC-MS/MS and Its Pharmacokinetics

WANG Xiaoyan , YANG Hanyu*, FAN Junhong, GUAN Xiaoduo, RONG Yanhua

2014, 45(12): 1163-1165.

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A LC-MS/MS method was established for the determination of rivaroxaban in dog plasma with diphenhydramine as the internal standard. An Acquity UPLC BEH C18 column was used with the mo bile phase of acetonitrile∶2 mmol/L ammonium acetate solution(containing 0.1％ formic acid)(35∶65). An electrospray ionization source (ESI) was applied and operated in the positive multiple reaction monitoring (MRM) mode with mass transitions of m/z 436.0→m/z 144.8 (rivaroxaban) and m/z 256.2 → m/z 167.2 (diphenhydramine). It was linear in the range of 20 -2 000 ng/ml. The intra- and inter-day RSDs were less than 15％. It was applied in dog pharmacokinetic study after oral administration of rivaroxaban tablets. The main pharmacokinetic parameters were as follows: tmax (1.27±0.49) h, cmax (577±248) ng/ml, t1/2(1.50±0.39) h, AUC0→t (1 778±838) h·ng·ml-1.

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Determination of Sarpogrelate Hydrochloride in Beagle Dog Plasma by LC-MS/MS and Bioavailability of Its Sustained-release Capsules

QIAO Hongqun, SUN Ling, WANG Yu, SHAO Qing, SHA Wenxiu

2014, 45(12): 1166-1169.

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A LC-MS/MS method was established for the determination of sarpogrelate hydrochloride (1) in Beagle dog plasma, and the bioavailability of 1 sustained-release capsules was investigated. An XTerra C18 column was used with the mobile phase of methanol∶10 mmol/L ammonium acetate solution (70∶30, pH 4.0). Aripiprazole was used as the internal standard. Detection was performed on ESI positive ion by multiple reaction monitoring (MRM) mode with the transitions of m/z 430.1→m/z 135.1 (1) and m/z 448.0→m/z 285.0 (aripiprazole). It was linear in the range of 0.5 - 5 000 ng/ml. The intra- and inter-day RSDs were no more than 4.31％ or 6.24％. A randomized crossover design was performed in 8 Beagle dogs. A single oral dose of 1 tablets (reference formulation, 100 mg) or 1 sustained-release capsules (test formulation, 150 mg) was administrated. The main pharmacokinetic parameters of the reference tablets
and the test capsules were as follows: cmax (3 736.45±335.68) and (1 263.78±228.83)ng/ml, AUC0→t (4 132.28±925.82) and (5 044.62±1 057.11)ng·h·ml-1, tmax (0.9±0.2) and (2.9±0.4)h, MRT (1.45±0.22) and (3.80±0.34)h. The relative bioavailability of the test formulation was 81.6％.

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Quality Evaluation of Schisandra chinensis Based on Combination of Fingerprint and QAMS

DOU Zhihua1, AN Liping2, SHI Kai1*, LUO Lin3, ZHANG Lin1

2014, 45(12): 1170-1174.

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An HPLC fingerprint of Schisandra chinensis was established, and a quantitative analysis of multicomponents by single marker (QAMS) method was developed for the simultaneous determination of six lignanoids in S. chinensis. A Lichrosphere C18 column was used, with the mobile phase of acetonitrile∶water by gradient elution, at the detection wavelength of 217 nm. Fingerprints of 12 batches of S. chinensis were determined and the similarities were over 0.990. The common mode of fingerprint was established and 24 common peaks were demarcated. By established QAMS method, schizandrol A was selected as the internal reference, then peak positions of schizandrol B, schisantherin A, deoxyschizandrin, schizandrin B and schizandrin C were definited by relative retentions, respectively. Content of schizandrol A in 12 batches of samples was determined by regression method and contents of the other components were calculated by relative correction factors (RCFs), respectively. It was linear for schizandrol A in the range of 0.09 -1.62 μg. Its recovery was 97.78％, with RSD of 2.32％.

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Determination of the Related Substances in Uliprisnil Acetate by HPLC

YOU Jun1, CAI Sheng2

2014, 45(12): 1174-1176.

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An HPLC method was established for the determination of the related substances in uliprisnil acetate. A Zorbax SB-C18 column was used with the mobile phase of acetonitrile∶water(containing 0.02％ TEA, adjusted to pH 6.5 by phosphoric acid)(60∶40), at the detection wavelength of 304 nm. The results showed that uliprisnil acetate and the related substances could be well separated. The low limits of detection for the specific related substances A, B, C
and D were 10 ng/ml, equivalent to 0.005％ of the test solution concentration.

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Evaluation of the Quality of Qiju Dihuang Pills (Condensed) by NIRS and HPLC Fingerprint

XIE Caixia, FAN Mingyue, BAI Yan*, LEI Jingwei, LIU Jianying

2014, 45(12): 1177-1180.

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The application of NIRS and HPLC fingerprint for the quality analysis of Qiju Dihuang pills (condensed) was studied. A NIRS clustering analysis method was used for the cluster identification of Qiju Dihuang pills (condensed) from different factories, and the results were contrasted with HPLC fingerprint, showing consistency between these two methods. With their advantages, NIRS and HPLC fingerprint could be used for the quality analysis as well as the identificaiton of Qiju Dihuang pills.

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Determination and HPLC Fingerprint of Fructus Forsythiae in Different Collecting Seasons

LEI Jingwei, ZHANG Qiang, XIE Caixia, DUAN Xiaoyan, BAI Yan*

2014, 45(12): 1181-1185.

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The content of phillyrin, forsythoside A, ethanol-extract and the hundred-grain weight of Fructus Forsythiae in different collecting seasons were determined. HPLC fingerprint of Forsythiae Fructus in different harvesting time showed that the similarity of green Forsythiae Fructus were more than 0.98, and the similarity of its different parts was high. However, the similarity of grown Forsythiae Fructus was different. The similarity of its shell was low, but that
of the seed was high. The results showed the optimum harvest time for green Forsythiae Fructus was late September, and the grown Forsythiae Fructus should be harvested before November.

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Research Status of the Inner Surface Durability of Glass Containers for Pharmaceutical Use

LI Ye, ZHANG Yilan*

2014, 45(12): 1186-1191.

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Glass delamination has emerged as a significant problem for the pharmaceutical industry, causing the recalls of numerous injectable drug products over the past several years. Therefore, people are paying more attention to the quality of glass containers. This paper briefly described the mechanisms of glass attack, outlined the main factors affecting the inner surface durability of glass containers and then introduced a suite of general methods and advanced
techniques utilized to characterize the containers which might have caused delamination after the accerlerated testing.

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Graphical Synthetic Routes of Dapagliflozin

ZHANG Shuaiyang, XU Bin, WANG Decai*

2014, 45(12): 1192-1195.

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The Revisions of Physical and Chemical Test Methods in General Chapters of Chinese Pharmacopoeia 2015 and Benefits Thereof

QIAN Chen, CHEN Jia, CHEN Guiliang*

2014, 45(12): 1195-1198.

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