Chinese Journal of Pharmaceuticals

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Synthesis of Volasertib

HUANG Daowei1,2, ZHANG Chuang1,2, JIN Xunqi1,2, BING Shaochang1,2, LI Jianqi1,2*

2015, 46(11): 1155-1157. https://doi.org/10.16522/j.cnki.cjph.2015.11.001

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The key intermediate, (R)-4-[(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydropterin- 2-yl)amino]-3-methoxybenzoic acid (8), was prepared from (R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7,8- dihydropteridin-6(5H)-one and 3-methoxy-4-aminobenzoic acid. Volasertib was synthesized from 1-(cyclopropylmethyl) piperazine (2) via reductive amination, hydrolysis and salt formation to give (1R,4R)-4-[4-
(cyclopropylmethyl)piperazin-1-yl]cyclohexylamine hydrochloride (5), which was subjected to condensation with 8 with an overall yield about 47％ (based on 2) and an HPLC purity of 99.7％.

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Synthesis of Prucalopride Succinate

GONG Yanchun, ZHOU Xipeng, PU Yiqing, REN Yingmei, YUAN Fang*

2015, 46(11): 1158-1160. https://doi.org/10.16522/j.cnki.cjph.2015.11.002

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1-(3-Methoxypropyl)piperidin-4-amine (4), the key intermediate of prucaloprid, was synthesized from piperidine-4-carboxylic acid (5) via esterification, N-alkylation, ammonification, and Hofmann rearrangement with an overall yield of 56％ (based on 5) and a purity over 99％. Prucalopride succinate for treatment of chronic constipation was synthesized from 4 by condensation with 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid, followed by salt formation with an overall yield of 39％ (based on 5) and a purity of 99.8％.

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Synthesis of Argatroban

LIU Kelei1, KANG Yanlong1, LI Jing2, ZHANG Dan2, MA Donglai2*

2015, 46(11): 1161-1164. https://doi.org/10.16522/j.cnki.cjph.2015.11.003

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Argatroban, an antithrombotic drug, was synthesized from (2R,4R)-4-methylpiperidine-2-carboxylic acid via esterification, condensation with (S)-2-[(tert-butoxycarbonyl)amino]-5-(3-nitroguanidino)pentanoic acid, deprotection of Boc group, condensation with 3-methylquinoline-8-sulfonyl chloride, hydrolysis, Pd/C-catalyzed hydrogenation and simultaneous deprotection, and purification with an overall yield about 12％ and a purity of 99.5%. This method was suitable for industrialization because of its simple operation and stable process.

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Synthesis of Ambrisentan

DING Tongjian, GU Huaping

2015, 46(11): 1165-1166. https://doi.org/10.16522/j.cnki.cjph.2015.11.004

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Ambrisentan for the treatment of pulmonary arterial hypertension was synthesized from 2-hydroxy- 3-methoxy-3,3-diphenylpropionic acid via resolution to give the crude (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid, which was subjected to condensation with 4,6-dimethyl-2-methylsulfonyl pyrimidine in the presence of lithium hydroxide monohydrate and purification by salt formation with ammonia with an overall yield about 32％.

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Synthesis of Zaltoprofen

ZHOU Yong, CHEN Wenhua

2015, 46(11): 1167-1168. https://doi.org/10.16522/j.cnki.cjph.2015.11.005

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Zaltoprofen was synthesized from 2-(3-carboxymethyl-4-phenylthiophenyl)propionic acid via esterification with methanol to give methyl 2-(3-methoxycarboxymethyl-4-phenylthiophenyl)propionate, which was subjected to cyclization with polyphosphoric acid, and hydrolysis with an overall yield of 89％ and a purity of 99.3％. This process was suitable for industrial production with simple operation and high yield.

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Synthesis of the Degradation Impurities of Vildagliptin

DING Jingwei, WANG Qiuyan, ZHANG Yong*

2015, 46(11): 1169-1172. https://doi.org/10.16522/j.cnki.cjph.2015.11.006

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To conduct the quality control of vildagliptin, three degradation impurities generated in the processes of pharmaceutical preparation and storage were synthesized. The chemical structures were confirmed by MS, 1H NMR and 13C NMR. They were 2-(3-hydroxyadamantan-1-yl)-1-iminohexahydropyrrolo[1,2-a]pyrazin-4(1H)- one (vildagliptin cyclic amidine, related substance A), 2-(3-hydroxyadamantan-1-yl)hexahydropyrrolo[1,2- a]pyrazin-1,4-dione (vildagliptin diketopiperizine, related substance B) and (S)-1-[2-(3-hydroxyadamantan-1- amino)acetyl]pyrrolidine-2-carboxamide (vildagliptin amide, related substance C).

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Expression of Recombinant Hyaluronidase from Streptococcus zooepidemicus in Escherichia coli and Its Enzyme Activity

CHEN Yifei, LI Qianqian*, RONG Shaofeng, Lü Sihan

2015, 46(11): 1173-1177. https://doi.org/10.16522/j.cnki.cjph.2015.11.007

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A hyaluronidase encoding gene (hyl) was amplified by PCR method using Streptococcus zooepidemicus MF002 genome as the template. The amplified fragment was inserted into a temperature-inducible expression vector named pBLMVL2. The recombinant plasmid was transformed into Escherichia coli BL21. Then, the recombinant hyaluronidase, which had a relative molecular mass of 9.7×104, was successfully expressed in recombinant E. coli named MF005. The results of temperature induction experiment and SDS-PAGE showed that the optimum temperature for hyaluronidase expression was 41.5 ℃. The crude hyaluronidase solution showed hydrolytic activity to hyaluronic acid after renaturation of inclusion body. The specific activity of crude hyaluronidase solution reached 2.3× 106 u/mg. The optimum enzymatic activity was achieved at 37 ℃ and pH 5.5.

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Quality Standard for Uighur Medicinal Herb Sophora alopecuroides L.

SHEN Xiaoli, ZHAO Peng, SULEYMAN Halik*

2015, 46(11): 1178-1180. https://doi.org/10.16522/j.cnki.cjph.2015.11.008

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A TLC method and an HPLC method were established for the identification of the Uighur medicinal herb Sophora alopecuroides L. and the determination of oxysophocarpine (1) and oxymatrine (2), respectively. The TLC results showed that compounds 1, 2 and sophoridine could achieve an effective separation with the developers of chloroform∶methanol∶concentrated ammonia solution (40∶10∶1). For the HPLC method, an NH2 column was used, with the mobile phase of acetonitrile∶absolute ethanol∶3％ phosphoric acid (80∶10∶10), at the detection wavelength of 205 nm. The calibration curves for both 1 and 2 were linear in the concentration range of 5 - 500 μg/ml. Their average recoveries were 100.5％ and 104.7％, with RSDs of 1.26％ and 1.32％, respectively.

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UPLC-DAD Fingerprints of the Anti-inflammatory Effective Parts Group of Smilax china

ZHANG Xiaoyan, HUANG Huihui, LUO Dan, YE Xiaochuan*, LIU Yanwen

2015, 46(11): 1181-1185. https://doi.org/10.16522/j.cnki.cjph.2015.11.009

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The UPLC-DAD fingerprints of the anti-inflammatory effective parts group of Smilax china were established. An Agilent Zorbax RRHD SB-C18 column was used, with the mobile phase of methanol∶acetonitrile (5∶1, A)∶0.1％ phosphoric acid (B) by gradient elution, at the detection wavelength of 290 nm in 0 - 25 min and 370 nm in 25 - 30 min. The common pattern of fingerprint containing 33 common peaks was obtained by determining 10 batches of the effective parts group of Smilax china. There were nine characteristic peaks identified as taxifolin, polydatin, oxyresveratrol, astilbin, resveratrol, quercitrin, engeletin, kaempferol and quercetin, respectively. The fingerprint similarities of 10 batches of effective parts group were all greater than 0.90.

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Preparation and Preliminary Pharmacodynamic Evaluation of Amino-modified Mesoporous Silica Nanoparticles Loaded with Andrographolide

TANG Tao1, ZANG Qiaozhen1, LONG Kaihua1, WANG Chunliu2, LI Ye2*

2015, 46(11): 1186-1191. https://doi.org/10.16522/j.cnki.cjph.2015.11.010

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The amino-modified mesoporous silica nanoparticles (NH2-MSN) were prepared by three methods, and their morphologies and structures were characterized. One of the prepared NH2-MSN, named as M3, with large specific surface area of 1 227.4 m2/g, pore volume of 0.67 m3/g, uniform size and oriented well-defined mesopores was selected. The average particle size and ζ potential of M3 were (148.1±3.1)nm and (37.04±0.22)mV. The drug loading and entrapment efficiency of andrographolide in the product prepared with M3 and andrographolide in the feed ratio of 1∶1 were (41.7±2.3)％ and (80.7±4.7)％. The pharmacodynamics of the product was preliminary investigated with the xylene-induced mouse ear edema model. The results showed that the anti-inflammatory effect of the product was superior to those of andrographolide suspensions and commercially available tablets.

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Preparation and Anti-tumor Activity of Protamine-deoxycholic Acid Nanocomplexes Loaded with Heparin Sodium

TENG Liping1, ZHANG Yirang2, FU Haitian2, CHEN Jinghua2*

2015, 46(11): 1192-1196. https://doi.org/10.16522/j.cnki.cjph.2015.11.011

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The protamine-deoxycholic acid conjugates with different conjugation degrees (DP1 - DP3) were synthesized through the reaction between protamine and N-hydroxysuccinimide ester of deoxycholic acid. The DP3 with conjugation degree of 32％ was used to prepare the stable nanocomplexes loaded with heparin sodium via electrostatic interaction. The particle size, ζ potential and drug loading capacity of the nanocomplexes with different feed weight ratios of DP3 to heparin sodium were investigated. The results showed that when the ratio of DP3 to heparin sodium was 1.5∶ 1, the loading capacity was nearly saturated. Under this preparation condition, the particle size, polydispersity index and ζ potential of the nanocomplexes were (136.0±2.5)nm, 0.164±0.005 and (+32.6±0.1)mV, respectively. Compared with the free heparin sodium, the above complexes could effectively induce intracellular delivery of heparin sodium into human lung adenocarcinoma A549 cells. The cytotoxicity assay in vitro showed that the nanocomplexes had a strong growth inhibition effect on A549 cells while DP3 had no marked cytotoxicity.

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Preparation of Membrane-modified Liposomes Loaded with Cyanidin-3-glycoside and Its Primary Protective Effect on HLECs

ZHANG Jing1, LUO Yunxia1, LIAO Zhenggen1, LUO Yun1, LI Xiang2*

2015, 46(11): 1197-1201. https://doi.org/10.16522/j.cnki.cjph.2015.11.012

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The cyanidin-3-glycoside (1) liposomes (1-L) were prepared by reverse-phase evaporation. The formulation was optimized by a central composite design-response surface method with entrapment efficiency as index. The results showed that the optimal parameters of 1-L were as follows: 1 concentration was 7.0 mg/ml, the weight ratio of phospholipid to cholesterol was 4, the volume ratio of organic phase to water phase was 4, and the concentration of phosphate buffer was 15 mmol/L. Then the optimal 1-L was coated with N-trimethyl chitosan (TMC) to obtain the title liposomes (1-TCL). The particle size, ζ potential and entrapment efficiency were (158.3±2.8)nm, (31.7±1.0)mV and (53.7±0.24)％, respectively. In vitro cumulative release at 36 h was about 40％ in artificial tear fluid. The human lens epithelium cells (HLECs) were pretreated by 1 solution, 1-L or 1-TCL, followed by oxidative damage with hydrogen peroxide and treated by corresponding samples again. Then the protective effects of 1 solution, 1-L and 1-TCL were investigated through above cell models. In comparison with the model group damaged by hydrogen peroxide, the cell viabilities were elevated by 64.7％ and 74.4％ in 1-TCL groups at 40 and 80 μmol/L. Compared with 1-L (40 μmol/L), more significant protective effects of 1-TCL were exhibited (P<0.05).

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Pharmacodynamic Investigation of Xelecoxib as a Selective COX-2 Inhibitor

AN Yongtong, SHEN Longhai

2015, 46(11): 1207-1212. https://doi.org/10.16522/j.cnki.cjph.2015.11.014

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The anti-inflammatory effects of xelecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, were investigated through the rat models of paw edema induced by carrageenan, arthritis by adjuvant and granuloma by cottonball with celecoxib, indomethacin or ibuprofen as the positive controls. Meanwhile, its analgesic effects in mice were investigated by hot plate and acetic acid induced writhing tests and its impact on the production of interleukin 1 (IL-1) in mice was also measured. The results showed that xelecoxib exhibited a significant anti-inflammatory effect in all above rat models as well as a significant analgesic effect in both pain models in mice at dose range of 1.25 - 10 mg/kg. The production of IL-1 in mice was also significantly inhibited by xelecoxib. Within the tested dose range, xelecoxib showed a certain dose-effect relationship.

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Pharmacokinetics and in vitro/in vivo Correlation of Ligustrazine Hydrochloride Gel Patches in Rats

SU Qing1,2, ZHAO Chongbo2, WU Chunjie2*, HE Yanfei1, FAN Jiao1

2015, 46(11): 1213-1216. https://doi.org/10.16522/j.cnki.cjph.2015.11.015

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The gel patches loaded with ligustrazine hydrochloride (1) were prepared. The in vitro transdermal behavior of the product was investigated with the excised SD rat skin as the barrier. The permeation rate of 1 from the product was 350.51 μg·cm-2·h-1 according to the in vitro penetration curves. The pharmacokinetics was also investigated with SD rats as model animals. According to the in vivo experimental data calculated by DAS 3.16 software, a twocompartment metabolic model was suitable for describing the pharmacokinetic behavior of 1 from the product in rats. The cmax, AUC0→∞ and tmax were (92.40±16.40)mg/L, (1 024.32±39.98)mg·L-1·h and (4.20±0.94)h, respectively. The in vivo accumulative absorption percentages were calculated by Loo-Riegelman method. A good in vitro/in vivo correlation was observed with the correlation coefficient of 0.941.

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Determination of Nolatrexed Dihydrochloride and Its Related Substances by HPLC

ZHOU Yimeng, ZHANG Qingwen, ZHOU Bin*

2015, 46(11): 1217-1219. https://doi.org/10.16522/j.cnki.cjph.2015.11.016

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An HPLC method was established for the determination of nolatrexed and its related substances. A TSK-C18 column was used with the mobile phase of 0.02 mol/L potassium dihydrogen phosphate solution (adjusted to pH 6.5 with sodium hydroxide solution)∶methanol (48∶52) at the detection wavelength of 226 nm. Nolatrexed and its related substances were separated well. It was linear in the concentration range of 0.005 - 0.5 mg/ml for nolatrexed dihydrochloride dihydrate. Its average recovery was 100.3％, with RSD of 0.13％.

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Chiral Separation and Determination of Rivaroxaban and Its Isomer by HPLC

CUI Ping1,2, JI Ancheng1, ZHANG Aihua1, DING Yimei1,2*

2015, 46(11): 1220-1222. https://doi.org/10.16522/j.cnki.cjph.2015.11.017

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An HPLC method was established for the chiral separation and determination of rivaroxaban and its optical isomer with (R)-configuration. An Chiral IB column was used, with the mobile phase of hexane (containing 0.1％ trifluoroacetic acid)∶isopropyl alcohol∶ethanol (60∶20∶20), at the detection wavelength of 250 nm. It was linear for (R)-isomer in the concentration range of 0.1 - 3.0 μg/ml. The average recovery was 99.0％, with RSD of 1.5％.

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Determination of Hydrazine in Rivaroxaban by Pre-column Derivatization-HPLC

ZHANG Mengmeng1, NI Xiang1, CHEN Mengke2, PAN Hongjuan1*

2015, 46(11): 1223-1226. https://doi.org/10.16522/j.cnki.cjph.2015.11.018

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A pre-column derivatization-HPLC method was established for the determination of hydrazine in rivaroxaban. Benzaldehyde was used as the derivatizing agent, and heptane as the extractant. A Dionex Acclaim 120 C18 column was used with the mobile phase of acetonitrile∶EDTA·2Na buffer(0.3 mg/ml)(70∶30) at the detection wavelength of 305 nm. It was linear for the hydrazine in the range of 0.05 - 0.50 μg/ml. Its average recovery was 98.3％, with RSD of 4.25％. Its limit of detection was 4.5 ng/ml.

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Determination of N-Octyl-D-glucamine in Dexketoprofen Trometamol Injection by HPLC-ELSD

LING Sa, LIANG Lu, DAI Zhengling, ZHANG Zhouju, ZHONG Qiaoni

2015, 46(11): 1227-1228. https://doi.org/10.16522/j.cnki.cjph.2015.11.019

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An HPLC-ELSD method was established for the determination of N-octyl-D-glucamine in dexketoprofen trometamol injection. An Agilent Zorbax C18 column was used, with the mobile phase of water (adjusted to pH 3.5 by glacial acetic acid)∶acetonitrile by gradient elution. An evaporative light scattering detector was used. It was linear for N-octyl-D-glucamine in the range of 0.005 - 0.25 mg/ml. The average recovery was 98.4％, with RSD of 1.1％.

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Qualitative and Quantitative Analysis for Milinqing Capsules

ZHOU Bin, WANG Yuanhui, SHU Juan

2015, 46(11): 1229-1231. https://doi.org/10.16522/j.cnki.cjph.2015.11.020

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Cortex Phellodendri in Milinqing capsules was identified by TLC. An HPLC method was established for the determiniation of phellodendrine hydrochloride in Milinqing capsules. A C18 column was used with the mobile phase of acetonitrile∶0.1％ phosphoric acid (containing 0.18％ sodium dodecyl sulfate, 31∶69) at the detection wavelength of 284 nm. The calibration curve was linear in the range of 5.1 - 51.0 μg/ml for phellodendrine hydrochloride. Its recovery was 100.7％, with RSD of 1.52％.

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Determination of Residual Organic Solvents in Gefitinib by GC

YANG Lixia1,2, ZHANG Sujuan1,2, ZHANG Xu1,2, SONG Qiannan1,2, LIANG Min1,2*

2015, 46(11): 1232-1235. https://doi.org/10.16522/j.cnki.cjph.2015.11.021

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A GC method was established for the determination of ten residual organic solvents and a starting material N-(3-chloropropyl)morpholine in gefitinib. DMF, DMSO and N-(3-chloropropyl)morpholine were quantitatively determined by direct sampling gas chromatography (D-GC) on a DB-624 column, with 1-methyl-2- pyrrolidinone∶chloroform (1∶99) as the solvent and temperature programmed control. Their average recoveries were 99.6％ - 101.8％, with RSDs less than 2.8％. Methanol, acetone, isopropanol, dichloromethane, tert-butyl methyl ether, n-hexane, chloroform and n-butanol were quantitatively determined by headspace gas chromatography (HS-GC) on a DB-624 column, with 1％ 1-methyl-2-pyrrolidinone aqueous solution as the solvent and temperature programmed control. The above eight organic solvents were completely separated. Their average recoveries were 98.2％ - 109.6％, with RSDs less than 4.2％.

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Progress of Novel Drug Delivery Systems of Insulin

WANG Liqun1, ZHAN Xiaoping2, CHEN Shaoxiong1, MAO Zhenmin2*

2015, 46(11): 1236-1244. https://doi.org/10.16522/j.cnki.cjph.2015.11.022

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Insulin is an important antidiabetic drug, subcutaneous injection is its traditional administration route in clinic. To simulate the curve of insulin secretion under normal physiological conditions and achieve good glycemic control, the rapid-, medium- and long-acting insulin analogues are usually used in combination. But longterm subcutaneous injection usually brings patients severe side effects. In order to improve patient compliance, novel non-injection administrations of insulin have been widely studied in recent years. Oral, nasal, pulmonary, transdermal, injectable in-situ gel and closed-loop delivery systems of insulin are reviewed in this paper. And the factors affecting insulin bioavailability and hypoglycemic effects in the process of developing novel delivery systems are also summarized.

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Preparation Methods and Characterization of Porous Polymer Microspheres

QIAO Hongmei

2015, 46(11): 1245-1249. https://doi.org/10.16522/j.cnki.cjph.2015.11.023

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Porous polymer microspheres are a kind of new functional material with larger specific surface area and plentiful pore structure. Because of the advantages of various preparation methods, controllable pore structure and ease of modification, they have been widely used in the fields of chromatography column packing and catalyst supports, etc. The preparation methods [suspension polymerization method, seed swelling polymerization method and membrane emulsification by Shirasu porous glass (SPG) membranes] and the corresponding pore forming mechanism are reviewed in this paper. And the characterization and applications of porous polymer microspheres are also briefly introduced.

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Graphical Synthetic Routes of Retigabine

SUN Zhijia1, ZHOU Bei2, WANG Shuobing1, ZHANG Guogang2,3*

2015, 46(11): 1250-1253. https://doi.org/10.16522/j.cnki.cjph.2015.11.024

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Introduction of the Tendering of Drugs in EU Countries and Its Implications for Chinese Drug Procurement

CHANG Feng, LIU Hongqiang*, LUO Xiuying

2015, 46(11): 1254-1258. https://doi.org/10.16522/j.cnki.cjph.2015.11.025

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