Chinese Journal of Pharmaceuticals

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Synthesis of Conivaptan Hydrochloride

ZHENG Dengyu, GAO Wenlei, ZHAO Jun, JIA Jingyu, CAO Shenghua?

2015, 46(09): 939-942. https://doi.org/10.16522/j.cnki.cjph.2015.09.001

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4-[(1,1'-Biphenyl)-2-ylcarboxamido]benzoic acid (12) was prepared from (1,1'-biphenyl)-2- carboxylic acid by amidation with 4-aminobenzoic acid. Conivaptan hydrochloride, a arginine vasopressin antagonist, was synthesized from methyl anthranilate (2) via sulfonylation, N-alkylation, intramolecular condensation, decyanation under acidic conditions, and bromination to give 1-tosyl-4-bromo-2,3,4,5-tetrahydro-5-oxo-1H-benzazepine, which was subjected to reaction with acetamidine hydrochloride and detosylation to give 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine, followed by amidation with 12 and slat formation with an overall yield of 25.5％ (based on compound 2).

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Synthesis of Selegiline Hydrochloride

ZHAO Xu, ZHANG Xuejing*, YAN Ming

2015, 46(09): 943-945. https://doi.org/10.16522/j.cnki.cjph.2015.09.002

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Selegiline hydrochloride, a selective B monoamine oxidase inhibitor, was synthesized from the chiral pool compound N-Fmoc-D-alanine via Friedel-Crafts acylation, deprotection and reduction to give (R)-α- methylphenethylamine, which was subjected to propargylation and reductive methylation with an overall yield of 41％.

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Synthesis of Cetilistat

SHEN Longying1, YAN Yan2, YANG Yajun1, PAN Xiandao1*

2015, 46(09): 946-947. https://doi.org/10.16522/j.cnki.cjph.2015.09.003

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Cetilistat was synthesized from 2-amino-5-methylbenzoic acid and cetyl chloroformate via acylation to give 2-[[(hexadecyloxy)carbonyl]amino]-5-methylbenzoic acid, which was subjected to intramolecular dehydrationcyclization in the presence of POCl3 with an overall yield of 90％ and purity over 99％. This one-pot method was simple and suitable for large-scale application.

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Synthesis of Tetrandrine

FU Zhihui1,2, YING Zhihong2, YAN Tuming1, ZHENG Yufei2, JIANG Xiaolin2

2015, 46(09): 948-949. https://doi.org/10.16522/j.cnki.cjph.2015.09.004

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Tetrandrine, a non-selective calcium channel blocker, was prepared by the reaction of demethyl tetrandrine with dimethyl sulfate in the presence of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) with a yield over 70％ and purity of 99.5％. The reaction was simple and complete. The resource utilization of Stephania tetrandra was increased.

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Synthesis of Amsacrine

CHEN Bing, GAO Fan, DONG Haiyang, WANG Jianhong, ZHAO Wenshan*

2015, 46(09): 950-951. https://doi.org/10.16522/j.cnki.cjph.2015.09.005

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Amsacrine, an antitumor drug, was prepared from 9-chloroacridine via nucleophilic aromatic substitution with 2-methoxy-4-nitroaniline to give 3-methoxy-4-(9-acridinylamino)nitrobenzene, which was subjected to reduction with stannous chloride to obtain 3-methoxy-4-(9-acridinylamino)aniline, followed by methanesulfonyl reaction with an overall yield of 39％.

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Computer-assisted Design, Synthesis and Activities of Aminopeptidase N Inhibitors

MOU Jiajia1, XU Wenfang2, WANG Qiang3, HE Yongzhi1, DENG Yanru1

2015, 46(09): 952-959. https://doi.org/10.16522/j.cnki.cjph.2015.09.006

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Sixty three compounds with L-arginine scaffold were designed and docked with aminopeptidase N (APN) by Sybyl/FlexX software. Sixteen new L-arginine derivatives with high docking scores were synthesized and their structures were confirmed by 1H NMR and MS. The results of in vitro anti-enzyme activity assay and in vitro antiproliferation assay showed that compound A22 exhibited comparable activity with the positive control (bestatin) and docked well with APN. So it could be used as a lead compound for the development of novel APN inhibitors.

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Mutation Breeding of γ-Polyglutamic Acid Producing Strain by Atmospheric and Room Temperature Plasma

CHEN Shuangxi, ZHANG Erchao, ZHANG Lele, XIA Qihao

2015, 46(09): 960-963. https://doi.org/10.16522/j.cnki.cjph.2015.09.007

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γ-Polyglutamic acid producing strain Bacillus subtilis HD11 was treated by atmospheric and room temperature plasma mutation, so as not to produce lipopeptides as one of the screening criteria. One mutant named HNCL1266 was obtained with the yield of γ-polyglutamic acid in shaking flask of 26 g/L, which was 30％ higher than that of HD11. The mutant strain showed high hereditary stability. In a 5 L fermentor, foams were suppressed effectively by addition of 0.2 g/L defoamer GPE. The yield of γ-polyglutamic acid reached to 30 g/L.

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Preparation and in vitro/in vivo Evaluation of Dextromethorphan Hydrobromide Oral Dissolvable Films

CHEN Fang, ZHANG Hua, ZHOU Zhen, WANG Jian

2015, 46(09): 964-969. https://doi.org/10.16522/j.cnki.cjph.2015.09.008

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Dextromethorphan hydrobromide (1) resin complexes with sodium polystyrene sulfonate ion exchange resin as carriers were pre-prepared to mask the bitter taste of 1, then adding hydroxypropyl methyl cellulose (HPMC) E3 and E15 as film-forming polymers to prepare oral dissolvable films for pediatric use. The results of differential scanning calorimetry and X-ray diffraction showed that 1 and the resin were combined through chemical bonds. The obtained films could dissolve within 1 min. The pH values and concentrations of potassium chloride solution had little effects on the dissolution of 1 from the films. The dissolution at 5 min was more than 80％ and the drug was completely released within 10 min in 0.4 mol/L potassium chloride solution. The results of pharmacokinetics in Beagle dogs indicated that the oral dissolvable films and commercial 1 granules showed similar pharmacokinetic characteristics and the relative bioavailability of the films was (101.9±24.0)％.

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Investigation of Spray Characteristics of Panax Notoginseng Saponins Nasal Spray

DENG Chunli1, WANG Xiaofei1,2, SHA Xianyi1, FANG Xiaoling1*

2015, 46(09): 970-974. https://doi.org/10.16522/j.cnki.cjph.2015.09.009

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The spray characteristics of the nasal spray loaded with Panax notoginseng saponins (1) were evaluated according to the methods recommended by FDA to improve the quality evaluation system for nasal sprays. The priming and repriming information was obtained through determining the changes of shot weight. The results showed that to ensure dose accuracy, the pump should be sprayed 5 times into the air (priming), and when the product was stored at room temperature within 1 month after priming, the pump should be sprayed 2 times (repriming). The droplet size distribution, spray pattern and plume geometry were investigated by laser particle size analyzer and SprayVIEW laser imaging system, respectively. The results showed that the droplet size of the nasal spray was mainly in the range of 25 - 180 μm, the longitudinal section of the spray was a sector with the angle of 23 - 28° while the cross section of the spray
was nearly circular with elliptical rate of 1.15 to 1.24. It indicated that 1 nasal spray had good spray characteristics. The methods used in this paper would help to improve the domestic quality evaluation system for nasal sprays.

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Influences of Molecular Weight and L/G Ratio of PLGA on Properties of Glycyrrhetinic Acid Microspheres

WANG Hong1, CAI Yaqin1, LIU Yanhua1,2,3, SUI Hong1,2,3, WANG Wenping1,2,3*

2015, 46(09): 975-979. https://doi.org/10.16522/j.cnki.cjph.2015.09.010

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The glycyrrhetinic acid-loaded microspheres were prepared by solvent evaporation method with five types of poly(lactic-co-glycolic acid) (PLGA) with different molecular weights (60 000, 90 000 and 120 000) and the lactide to glycolide ratio (L/G ratio, 50/50, 65/35 and 80/20) as carriers. The effects of different types of PLGA on drug loading and encapsulation efficiency of the microspheres were investigated. The in vitro erosion performance and drug release of the obtained microspheres and pH value changes of the medium at different sampling points were also analyzed. The results showed that there was no significant differences in drug loading and encapsulation efficiency among five kinds of microspheres. The erosion rate and drug release rate were decreased with the increasing of molecular weight or L/G ratio of PLGA. In the test for microspheres with PLGA 60000 (65/35 or 80/20) as carriers, the decline rates of pH values of the medium were significantly decreased, and the pH values were nearly not declined after 30 days. It indicated that the in vitro performance of drug-loaded PLGA microspheres was closely related to molecular weight and L/G ratio of PLGA.

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Effect of Methocel^TM VLV on Quality Improvement of Coating Preparations Loaded with Heat- and Moisture-sensitive Drugs

LU Zhenju, WANG Chao, CHEN Fei, HE Yingjie, GAO Hao*

2015, 46(09): 980-984. https://doi.org/10.16522/j.cnki.cjph.2015.09.011

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Methocel^TM VLV is a novel low molecular weight version of hypromellose with the viscosity range of 2.3 - 3.3 mPa·s. The evaporation rates of water from different polymer solutions [Methocel^TM VLV, Methocel^TM E5LV and polyvinyl alcohol (PVA) EG-05P] were compared. The effects of different polymers as coating material on appearance and drug content of the prepared coating tablets were investigated with eugenol and coenzyme Q10 as model drugs. Among
the three polymers, Methocel^TM VLV had the fastest evaporation rate of water, which meant that this material had the weakest water retention capability. So, it could be used in aqueous film coating process under lower temperature (<30 ℃) due to this property. Compared with Methocel^TME5LV and PVA EG-05P, appearance and drug content of the eugenol or coenzyme Q₁₀ tablets with Methocel^TMVLV as coating material had no significant changes, which indicated that it could improve the stability of heat- and moisture-sensitive drugs.

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In situ Intestinal Absorption Characteristics of Alisols Effective Fraction in Rats

CHENG Zhihong, SONG Dingzhong, YUAN Jie, HAO Wusi, HOU Huimin*

2015, 46(09): 985-990. https://doi.org/10.16522/j.cnki.cjph.2015.09.012

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To investigate the intestinal absorption kinetics of alisols effective fraction, the in situ intestinal perfusion model was constructed in rats with phenol red as a volume indicator. The concentrations of alisol A (1), alisol A 23-acetate (2) and alisol A 24-acetate (3), the main constituents of alisols effective fraction, in intestinal perfusion fluids were measured by HPLC. The influences of different segments of intestine, alisol concentrations, pH value and perfusion flow rate of perfusion fluids on the absorption of three ingredients were also evaluated. The results showed that 1, 2 and 3 could be absorbed effectively in whole intestine with no significant differences. The apparent permeability coefficients (Papp) at different intestinal segments (duodenum, jejunum, ileum and colon) had no significant differences. The Papp values of the three ingredients were relatively high when their concentrations were in the ranges of 230 - 340 μg/ml
and the pH value of perfusion fluid was 6.8, which indicated that these situations were beneficial for drug absorption. In addition, the Papp values were not affected significantly when the perfusion flow rate increased from 1 ml/min to 10 ml/min.

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Determination of Imatinib in Human Plasma by LC-MS/MS and the Bioequivalence Evaluation

PAN Jing, GONG Zhicheng*

2015, 46(09): 991-994. https://doi.org/10.16522/j.cnki.cjph.2015.09.013

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A LC-MS/MS method was established for the determination of imatinib in human plasma, and the pharmacokinetic parameters of imatinib mesylate capsules (test and reference preparations) were calculated for the evaluation of their bioequivalence in healthy volunteers. A Thermo BDS C18 column was used, with the mobile phase of acetonitrile∶0.2％ formic acid (containing 20 mmol/L ammonium acetate)(88∶12). Mass spectrometry was peformed in the multiple reaction monitoring (MRM) mode with positive electrospray ionization. The monitored transitions of imatinib and the internal standard erlotinib were m/z 494.3→m/z 394.2 and m/z 394.2→m/z 278.1, respectively. A twoperiod randomized crossover trial was conducted. The major pharmacokinetic parameters of the test and reference preparations were calculated as follows: cmax (1 854±592) and (1 865±606)ng/ml, tmax (4.0±1.0) and (4.4±1.4) h, t1/2
(13.1±2.4) and (12.7±1.8) h, AUC0→t (29 783±12 514) and (30 376±14 323)ng·h·ml-1, respectively. The results showed that the two formulations were bioequivalent.

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Determination of Nine Compounds in Huanglian Shangqing Tablets by HPLC Combined with Wavelength Switching Method

HAO Chengyi, FENG Bo, GUO Shuying, ZHU Heyun, ZHANG Huifeng

2015, 46(09): 995-998. https://doi.org/10.16522/j.cnki.cjph.2015.09.014

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An HPLC combined with wavelength switching method was established for the determination of nine main components in Huanglian Shangqing tablets. A Dikma Platisil ODS column was used, with the mobile phase of methanol∶0.1％ phosphoric acid by gradient elution. The detection wavelength was switched for chlorogenic acid and baicalin (at 327 nm), geniposide (at 240 nm), berberine hydrochloride, emodin, chrysophanol, aloe-emodin, rhein and physcion (at 254 nm), respectively. The results showed that all the nine components were well separated, and the linear relationships were good in their corresponding ranges. Their average recoveries were 98.8％ - 100.7％, with RSDs of 0.4％ - 1.3％.

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Simultaneous Determination of 29 Elements in Traditional Chinese Medicines by Inductively Coupled Plasma Mass Spectrometer (ICP-MS)

LI Limin1,2, XIA Jing1, ZHANG Su1, WANG Meibo1, JI Shen1*

2015, 46(09): 999-1003. https://doi.org/10.16522/j.cnki.cjph.2015.09.015

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An inductively coupled plasma mass spectrometer (ICP-MS) method was established for the determination of 29 elements, such as Be, Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Ru, Pd, Ag, Cd, Sn, Sb, Te, Ba, Nd, Dy, Er, Ir, Hg, Tl, Pb, and U in 23 kinds of traditional Chinese medicines. The samples were digested by nitric acid∶ hydrochloric acid (4∶1) with microwave. The matrix and spectra interference of the ICP-MS were eliminated by online internal standard addition and octopole reaction/collision cell. Normal and helium collision reaction mode were selected for different elements. The RSDs of repeatabilities for 29 elements in different parts of traditional Chinese mdicines were all less than 32.4％. Their average recoveries were in the range of 69.8％ - 121.8％. Their limits of detection were 0.000 3 - 0.609 mg/kg.

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Determination of the Genotoxic Impurity in Apixaban by LC-MS

WANG Huijun1, PAN Hongjuan1, LIU Chao2, HOU Jian2*

2015, 46(09): 1004-1006. https://doi.org/10.16522/j.cnki.cjph.2015.09.016

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A LC-MS method was established for the determination of the genotoxic impurity, 3-morpholino-1- [4-(5-chloropentamido)phenyl]-5,6-dihydropyridin-2(1H)-one (2), in apixaban. A Waters Xterra RP18 column was used, with the mobile phase of 0.01 mol/L ammonium acetate buffer∶acetonitrile by gradient elution. The MS detection was carried out by monitoring m/z 392.2 in selective ion monitoring (SIM) mode with positive electrospray ionization. It was linear for 2 in the range of 10 - 100 ng/ml. The average recovery was 101.5％, with RSD of 1.7％. The LLOD and LLOQ were 2.015 and 5.038 ng/ml, respectively.

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Determination of Four Enantiomers in Tofacitinib Citrate by HPLC

WANG Yanjiao, LIU Yongjin, GUO Wenmin*, BAI Peifeng, HE Ying

2015, 46(09): 1007-1009. https://doi.org/10.16522/j.cnki.cjph.2015.09.017

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An HPLC method was established for the determination of four enantiomers in tofacitinib citrate. A Chiralpak IC column was used with the mobile phase of methyl tertbutyl ether∶ethanol∶diethylamine (70∶30∶ 0.1) at the detection wavelength of 280 nm. The resolutions of tofacitinib citrate enantiomers were greater than 2.0. The calibration curves of four enantiomers were all linear in the ranges of 0.1 - 120 μg/ml. The recoveries were above 99.0％, with RSDs less than 1.5％. Their low limits of quantification were all 0.1 μg/ml.

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Determination of Cinepazide Maleate and Its Related Substances by HPLC

ZHOU Yimeng, ZHOU Bin*

2015, 46(09): 1010-1012. https://doi.org/10.16522/j.cnki.cjph.2015.09.018

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An HPLC method was established for the determination of cinepazide maleate and its related substances. A Phenomenex HyperClone BDS C18 column was used with the mobile phase of 0.3％ triethylamine (adjusted to pH 7.5 with phosphoric acid)∶methanol (49∶51) at the detection wavelength of 230 nm. Cinepazide maleate and its related substances were well separated. The calibration curve for cinepazide maleate was linear in the concentration range of 0.01 - 1 mg/ml. The average recovery was 99.83％, with RSD of 0.37％.

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Determination of Related Substances in Rabeprazole Sodium Bulk Drug by HPLC

SONG Dongmei, LIU Lu, JIANG Wenming, YANG Yongjian*

2015, 46(09): 1013-1016. https://doi.org/10.16522/j.cnki.cjph.2015.09.019

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An HPLC method was established for the determination of the related substances in rabeprazole sodium bulk drug. A C18 column was used, with the mobile phase of 15 mmol/L disodium hydrogen phosphate solution (adjusted to pH 6.0 with phosphoric acid)∶acetonitrile (60∶40), at the detection wavelength of 290 nm. The calibration curves of rabeprazole sodium and six related substances were linear in the ranges of 0.04 - 10 μg/ml, while it was linear in the range of 0.04 - 5 μg/ml for 2-[[(4-methoxy-3-methylpyridin-2-yl)methyl]sulfinyl]-1H-benzimidazole. The recoveries for seven related substances were 101.34％ - 107.90％, with RSDs of 1.00％ - 6.35％.

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Determination of Pramipexole Patch and Its Related Substances by HPLC

PU Tingting1, CHEN Haishuo1, WANG Qing1*, YANG Yuexin2, DING Xue1

2015, 46(09): 1017-1020. https://doi.org/10.16522/j.cnki.cjph.2015.09.020

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An HPLC method was established for the determination of pramipexole patch and its related substances. A Thermo Hypersil BDS C18 column was used, with the mobile phase of 10 mmol/L potassium dihydrogen phosphate buffer (containing 20 mmol/L sodium heptanesulfonate, adjusted to pH 3.0 by phosphoric acid)∶acetonitrile (78∶22), at the detection wavelength of 264 nm. It was linear for pramipexole in the range of 0.5 - 100 μg/ml. The average recovery was 98.24％, with RSD of 1.71％.

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Research Situation of Liposomal Dry Powder Inhalations

ZHENG Luxia1,2, CHEN Gang2, CHEN Guiliang2, WANG Hao1

2015, 46(09): 1021-1026. https://doi.org/10.16522/j.cnki.cjph.2015.09.021

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Liposomal dry powder inhalations have shown many promising features for pulmonary drug administration, such as targeted and sustained drug delivery, reduced local and systemic toxicity and stability in storage. The characterization, development, application, preparation, quality evaluation, toxicology assessment as well as some existing problems of liposomal dry powder inhalations are reviewed in this paper.

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New Institutional Economic Theoretical Research on Separation Management of Drug Marketing Authorization and Production License

CHEN Yongfa, WU Lin, SHAO Rong

2015, 46(09): 1034-1038. https://doi.org/10.16522/j.cnki.cjph.2015.09.023

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Research and Evaluation of the Change of Sterilization Process of Injections Based on the CTD Document

LI Sen1, ZHANG Jingchen2*

2015, 46(09): 1039-1042. https://doi.org/10.16522/j.cnki.cjph.2015.09.024

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