Chinese Journal of Pharmaceuticals

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Synthesis of Nafoxidine

CHEN Yunxiang1, HUANG Yangwei2, ZHAO Xueqing2*, LI Zhongming1

2014, 45(6): 501-503.

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Nafoxidine, an intermediate of lasofoxifene was synthesized from 6-methoxy-2-phenyl-1-tetralone and nonafluorobutanesulfonyl fluoride, followed by coupling with [4-[2-(pyrrolidin-1-yl)ethoxy]phenyl]magnesium bromide at room temperature in the presence of CuCN·2LiCl, with Fe(acac)3 as a catalyst, with an overall yield of 83.5％.

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Synthesis of D-Dopa

LIU Yuxue1, WANG Xiang2, WANG Li2, GAO Jun2, SHANG Muhong3*

2014, 45(6): 504-506.

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D-Dopa was synthesized from 3,4-dihydroxybenzaldehyde and N-acetylglycine by condensation, dehydration and ring-opening reaction with methanol to give methyl 2-acetamido-3-(3,4-diacetoxyphenyl)acrylate, which was subjected to asymmetric hydrogenation in the presence of [(R,R)-Ph-BPE-Rh-COD]BF4 to afford (R)-methyl-2-acetamido-3-(3,4-diacetoxyphenyl)propionate, followed by hydrolysis with hydrochloric acid with an overall yield of about 16％.

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Synthesis of Lenvatinib

SUN Huan1, LI Lin1*, HE Ruihong2, LIU Mengchun1, LIU Weifeng1

2014, 45(6): 507-510.

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4-Chloro-7-methoxyquinoline-6-carboxamide(8) was synthesized from methyl 4-amino-2-methoxybenzoate(4) by condensation with Meldrum's acid, ring closure, chlorination and aminolysis. While the intermediate 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea(12) can be obtained from ο-nitrochlorobenzene by reduction, translocation, acylation and substitution. Lenvatinib, an antitumor agent, was synthesized from 8 and 12 by nucleophilic substitution with an overall yield of about 39％(based on compound 4) and an HPLC purity of 99.8％.

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Synthesis of Folic Acid

CHEN Wenhua

2014, 45(6): 511-512.

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Folic acid was synthesized by reaction from 1,1,3-trichloropropan-2-one, N-(4-aminobenzoyl)-Lglutamic acid and 2,4,5-triamino-6-hydroxypyrimidine sulfate to afford the crude product, followed by acid precipitation and alkali refining. The mother liquor obtained in the preparation of the crude folic acid was vacuum distillated to afford
1,1,3-trichloropropan-2-one solution, and the recovered solution could be recycled and used for more than 10 times with the average yield of 65.2％ and purities of 97.8％ - 98.6％.

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Synthesis of Related Substances of Gefitinib

WU Lihong, ZHANG Yanqiao, LIANG Min, LIU Yang, ZHENG Ligang

2014, 45(6): 513-516.

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To perform the quality control of the gefitinib, four related substances recorded in quality specifications were prepared, and their structures were confirmed by 1H NMR, 13C NMR and MS. These substances were N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]-N-[3-(morpholin-4-yl)propyl)quinazolin-4-
amine(A), N-(4-chloro-3-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine(B), 7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4(3H)-one(C), and N-(3,4-dichlorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine(D).

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Synthesis of Cefpirome Sulfate

LI Mingjie, CHAI Qian, HOU Shanbo, SU Guo

2014, 45(6): 517-518.

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Acylation of 7-ACA with S-benzothiazol-2-yl 2-(2-aminothiazol-4-yl)(methoxyimino)thioacetate (MAEM)afforded cefotaxime, which underwent 3-substitution by cyclopentano[b]pyridine and then salt formation to obtain cefpirome dihydroiodide, followed by salt exchange with sulfuric acid to give cefpirome sulfate in 62％ overall yield.

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New Application of Merrifield Resin in the Synthesis of Structural Modified Peptides

YANG Xiaoxiao, LIN Hao, WANG Dexin*

2014, 45(6): 519-524.

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Based on Merrifield resin, a new strategy, HOP (hybrid orthogonal protocol), was explored. In this strategy, Fmoc protocol and Boc protocol were matched on Merrifield resin in one batch synthesis. By this way the key intermediate, naked peptidyl-resin, could be prepared just after TFA treatment which removed side-chain protecting groups(tBu, Trt, Boc, Pbf…), but the peptidyl-resin linkage was retained. Based on the naked peptidyl resin, different kinds of products with C-terminal N-substituted peptide amides and side-chain lactam bonding cyclopeptides could be easily produced with more reasonable yields and purities than that from conventional protocol of SPPS.

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Directed Evolution of Plectasin by Error-prone PCR

ZHANG Qi, HU Youjia, CHEN Xiping, XIE Liping*

2014, 45(6): 525-530.

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The gene coding plectasin mature peptide was optimized according to the E.coli codon usage bias. Error-prone PCR was applied to evolve this peptide by usage of EX Taq DNA polymerase and adding Mn2+ and different concentrations of Mg2+. Meanwhile, the amplification program was changed to improve the mutation rate. The PCR product was cloned and transformed into E.coli and 200 mutants were screened. After sequence identification and antimicrobial activity screening, a mutant M-1 was obtained. It was revealed that there was one amino acid substitution. The 31-alanine was substituted by arginine. According to the simulated protein of mutant M-1 peptide, the mutation site was located at β-fold, near to the center of active site, which made it easier for the specific binding to lipidⅡ. The mutant peptide M-1 was then purificated. The results of antimicrobial activity study showed that the activity of mutant peptide M-1 was 2 times of plectasin.

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Optimization of Culture Medium for Polymyxin B Production

MA Chuanchuan, WEI Xiaodong, ZHAO Bo, NA Ke, ZHAO Wenjie*

2014, 45(6): 531-533.

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A single factor experiment and response surface methodology were employed for the optimization of culture medium for polymyxin B production from Bacillus polymyxa. The optimum culture medium was verified on the 7 L fermentation tank as follows: wheat flour of 6.7％, corn steep powder of 0.3％, glucose of 0.48％, ammonium sulfate of 0.9％, monopotassium phosphate of 0.03％ and calcium carbonate of 0.03％. Under such conditions, the yield of polymyxin B was 0.95 g/L in shaking flasks, 120.9％ higher than the original, and it was 1.06 g/L in the 7 L fermentation tank.

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Preparation of Venlafaxine Hydrochloride Sustained-release Capsules

LIANG Chaofeng1, LIU Ying1, HUANG Chunhui1, HUANG Yunran1, CHEN Tongkai2*

2014, 45(6): 534-538.

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The pellet cores loaded with venlafaxine hydrochloride were prepared by extrusion-spheronization technique. The formulation and process parameters were optimized with single factor test and Box-Behnken design. The optimal process was as follows: extrusion speed was 35 r/min, the amount of wetting agent was 25％, spheronization speed was 1 050 r/min and the spheronization time was 8 min. The measured values of yield and roundness for the drugloading pellet cores prepared by the optimal process were close to the model predicted values. The isolation layer and sustained-release layer were coated on the above pellet cores by fluid bed coating process. Then the obtained particles were filled into capsules to get a sustained-release formulation taken only once a day for water-soluble drug. The in vitro
release was carried out with the commercial sustained-release capsules (Effexor XR®) as a reference preparation. The results showed that the release profiles of three self-made products were all consistent with the reference preparation according to the similarity factor (f2) values which were all over 50.

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In vitro Percutaneous Penetration of Vinpocetine Ethosomal Gel

MAO Yanting1,2, CHEN Xiaofeng1, CHEN Haiyan1, TAO Jun2, ZHAO Yongxing2*

2014, 45(6): 539-542.

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The vinpocetine (1) ethosomes were prepared by ethanol injection-sonication method. The formulation was optimized by orthogonal test with encapsulation efficiency and permeation rate of the ethosomes as the indexes. The encapsulation efficiency, drug content and permeation rate of the optimal ethosomes contained 0.45％ 1, 45％ ethanol, 3％ lecithin and sonication for 3 min were (79.5±1.8)％, (3.52±0.03)mg/ml and(8.15±0.05)μg·cm-2·h-1, respectively. Then the optimal formulation was processed to hydrogel to improve the bioadhesion of ethosomes. The stable penetration rates (Jss) of 1 ethosomes and its gel as well as 1 saturated solution and its gel were investigated and compared with the excised rat skin as the barrier. The results of the latter three products were (3.56±0.13), (1.15±0.14) and (0.53±0.03)μg·cm-2·h-1, respectively.

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Preparation and in vitro Drug Release of Molecularly Imprinted Polymer of Enrofloxacin

WANG Dongyun, LI Qing, DU Pan, GE Yanru, QI Xueyong*

2014, 45(6): 543-547.

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The molecularly imprinted polymers (MIPs) of enrofloxacin were synthesized with enrofloxacin as the template, methacrylic acid as functional monomer and trimethylolpropane trimethylacrylate as cross-linker. The synthesis conditions were optimized via adsorption experiment. The products were subsequently characterized by scanning electronic microscopy, IR analysis and adsorption test. Moreover, the in vitro release behaviors of these products in four media with different pH values were determined. When the ratio of templates∶functional monomer∶cross-linker was 1∶8∶6, the binding property of MIPs was better than others. Under the optimal conditions, the apparent maximum number of the binding sites was as high as 66.8 mg/g as revealed by Scatchard analysis. The in vitro release of the obtained MIPs reloaded with enrofloxacin was in a pH-dependent manner with a serious burst release.

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Preparation of Uygurian Medicine Compound Juweina Cream

ZHANG Rong1, XING Jianguo2*, HE Chenghui, LIU Xuanlin2

2014, 45(6): 548-551.

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To improve the dosage form of Uygurian medicine compound Juweina ointment, the formation and stability of the o/w and w/o creams of compound Juweina with different matrices were compared. The results showed that the optimal formulation was the o/w cream with stearic acid 9 g, monoglyceride 6 g, liquid paraffin 12 g, solid paraffin 1 g, lauryl sodium sulfate 1 g, glycerol 8 g and ethylparaben 0.1 g. The influences of different penetration enhancers and their combinations on the transdermal behavior of hederagenin through the excised mouse skin were investigated with Franz diffusion cell. The results showed that the combination of 2％ azone and 4％ propylene glycol had the best enhancement effect.

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Pharmacokinetics of Amoxicillin/Clavulanate (16︰1) Sustained-release Tablets in Beagle Dogs

HUO Liru, XIE Shaofei*, ZHANG Fengyi, ZHANG Hanchun

2014, 45(6): 552-555.

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A single dose, two period cross over experiment design was conducted to evaluate pharmacokinetic behavior after oral administration of amoxicillin/clavulanate (16︰1) sustained-release tablets to Beagle dogs. The drug concentration was determined by LC-MS/MS. The main pharmacokinetic parameters of amoxicillin in test and reference preparations were as follows: cmax (34.39±8.04) and (33.56±5.74) μg·ml-1, tmax (1.75±0.25) and (1.50±0.50) h, t1/2 (1.66±0.44) and (1.80±0.55) h, AUC0→∞ (125.51±16.79) and (140.49±28.44) μg·h·ml-1. The main pharmacokinetic parameters of clavulanate in test and reference preparations were as follows: cmax (4.08±0.21) and (4.01±0.53) μg·ml-1, tmax (1.5±0.25) and (1.5±0.25) h, t1/2 (1.05±0.18) and (0.97±0.17) h, AUC0→∞ (9.01±0.55) and (9.93±1.24) μg·h·ml-1.
The results indicated that the pharmacokinetic behaviors of test and reference preparations were identical.

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Pharmacokinetics of Cinnamic Acid, Liquiritin and Glycyrrhetinic Acid in Kouyanqing Granules

ZHANG Zijian1, WANG Jing2, GUO Panpan3, DONG Lihua3, WANG Chunying3*

2014, 45(6): 556-559.

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A LC-MS/MS method was developed and validated with sulfamethoxazole as the internal standard (IS) for the determination of cinnamic acid, liquiritin and glycyrrhetinic acid in rat plasma after ig. administration of Kouyanqing granules. A C18 column was used with the mobile phase of methanol︰0.05％ formic acid by gradient elution. The analytes were detected using a hybrid quadrupole linear ion trap mass spectrometer that was equipped with an electrospray ionization source in the negative ion and multiple-reaction monitoring scanning modes. The pharmacokinetic parameters of cinnamic acid, liquiritin and glycyrrhetinic acid in rat plasma were as follows: cmax of (105.22±9.51), (24.95±3.50) and (26.40±3.60) ng·ml-1, tmax of (20±0) min, t1/2 of (125.60±10.61), (176.02±15.30) and (84.10±
7.50) min, AUC0→∞ of (1.76×104±0.19), (1.93×103±0.28) and (4.14×103±0.46)ng· min·ml-1, respectively.

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Determination of Related Substances in Esomeprazole Magnesium Enteric-coated Capsules by HPLC

CHEN Fangxiao, WANG Lei, ZENG Huanxiang, LAI Qingkuan, HUANG Huai

2014, 45(6): 560-563.

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An HPLC method was established for the determination of the related substances in esomeprazole magnesium enteric-coated capsules. An XBridge C18 column was used with the mobile phase of acetonitrile︰pH 7.6 phosphate buffer︰water (10︰10︰80, A) and acetonitrile︰pH 7.6 phosphate buffer︰water (80︰1︰19, B) by gradient elution, at the detection wavelength of 302 nm. The calibration curves were linear for esomeprazole magnesium and its related substances, H118/87, H168/66, H431/41 and H193/61, in the ranges of 0.04 - 2.0, 0.04 - 2.0, 0.04 - 2.0, 0.05 - 10.0 and 0.04 - 2.0 μg/ml. Their average recoveries were 99.5％, 96.7％, 99.8％, 98.9％ and 99.3％, with RSDs of 0.45％, 0.20％,0.78％, 0.43％ and 0.41％, respectively.

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Determination of Related Substances In Levodopa and Benserazide Hydrochloride Capsules by HPLC

LIU Guangjuan, SUN Ningyun, CHEN Qiufen, ZHANG Jundong*

2014, 45(6): 564-566.

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An HPLC method was established for the determination of the related substances in levodopa and benserazide hydrochloride capsules. A Merck Purospher star RP-C8 column was used, with the mobile phase of 5.95 mg/ml potassium dihydrogen phosphate solution (containing 1.525 mg/ml sodium decanesulfonate)︰acetonitrile (79︰21), adjusted to pH 3.5 with phosphoric acid, at the detection wavelength of 220 nm. The resolution between the peaks of benserazide hydrochloride and related substances was good. The calibration curves for benserazide hydrochloride, related substances A and B were linear in the concentration ranges of 0.25 - 50, 1.2 - 30 and 0.15 - 50 μg/ml. The average recoveries of related substances A, B and C were 99.7％, 108.5％ and 102.5％, with RSDs of 5.40％, 2.89％ and 3.14％, respectively.

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Determination of Sirolimus and Its Release Rate in Drug-eluting Stents by HPLC

XU Wenjun1, ZHANG Quanying2, WANG Meng2

2014, 45(6): 567-569.

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An HPLC method was established for the determination of sirolimus and its release rate in drugeluting stents. It was extracted from stents by the addition of 0.01 mol/L phosphate buffer (pH 6.0)︰0.02％ BHT acetonitrile solution (65︰35). A Symmetry ShiledTM RP18 column was used, with the mobile phase of methanol︰
acetonitrile︰water (17︰50︰33) at the detection wavelength of 278 nm. The calibration curve was linear in the range of 0.5 - 16.0 μg/ml. The average recovery was (100.7±0.7)％, with RSD of 0.7％. The results showed that in vivo cumulative drug-release rate of drug-eluting stents were 49.8％ at 7 days and 82.8％ at 90 days.

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Determination of Mianserin Hydrochloride Tablets by HPLC

ZHU Li1, JIA Shoushi2, ZHANG Liancheng2*

2014, 45(6): 570-572.

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An HPLC method was established for the determination of content and its related substances of mianserin hydrochloride tablets. A Diamonsil C18 column was used with the mobile phase of methanol︰water (35︰65) at the detection wavelength of 279 nm. It was linear in the concentration range of 6.0 - 90.0 μg/ml. The average recovery was 99.8％, with RSD of 0.53％.

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Qualitative Detection of Shiwei Xiaoshi San by TLC and Determination of Cinnamic Acid and Gallic Acid by HPLC

ZHANG Xingfu1, LIU Yuanhui2, LUO Guifa1, FAN Yingying1

2014, 45(6): 573-576.

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The qualitative and quantitative quality controls of Shiwei Xiaoshi San were established. A TLC method was established for the qualitative detection of Cortex Cinnamomi Cassiae, Piper nigrum L. and Fructus Piperis Longi.. An HPLC method was conducted for the determination of cinnamic acid and gallic acid. The characteristic spots of cinnamic aldehyde in Cortex Cinnamomi Cassiae and piperine in Piper nigrum L. and Fructus Piperis Longi. could be distinguished by TLC. The calibration curves of cinnamic acid and gallic acid were linear in the ranges of 1.01 - 50.52 and 2.03 - 101.64 μg/ml. The average recoveries were 101.2％ and 102.4％, with RSDs of 2.18％ and 1.25％.

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Analysis of Heat Transfer Characteristics on a Basic Medicinal Water Distiller Unit

XIU Yun1, CHEN Lan1*, LIU Yufeng2, CHEN Shunhua2, GAO Yunwei3

2014, 45(6): 577-581.

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On the basis of the trend of energy saving and emission reduction, the heat transfer performance of medicinal water distiller (MWD) for producing distilled water and water for injection has been attracting more and more attentions. Based on the basic structure and heat transfer characteristics of tubular MWD, a lab-scale set-up were built and experiments were carried out to determine the heat transfer coefficient and pressure drop by taking water and steam as the heat transfer medium. Furthermore, a three-dimensional simplified model of the basic unit for water-steam flow and heat transfer was established. The numerical simulation on vertical corrugated tubes and smooth tubes under different working conditions was investigated, and the temperature, velocity and pressure distributions were obtained, respectively. The comparative analysis was done between the numerical and the experimental results and the reliability of the simulation was thus proved. This paper provided an important and useful technical method for MWD design and application.

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Research Progress in Extractables and Leachables of Metered Dose Inhalers

MA Juan1, YANG Yongjian2, ZHANG Qiming3, JIN Fang4*

2014, 45(6): 589-594.

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As metered dose inhalers (MDIs) are special drug-device combination products, there is a high possibility of occurring the interaction between the formulation and device. Then there exists a potential threat on the drug safety. Therefore, it is necessary to investigate the extractables and leachables in MDIs. On the basis of the existing research results and ideas of the compatibility study of drug and packages, the progress of extractables and leachables in MDIs as well as their analytical methods is reviewed in this paper.

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Graphical Synthetic Routes of Regadenoson

WU Liqian, WANG Jiahui, GU Honglei, ZHANG Fuli*

2014, 45(6): 595-598.

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Progress in Global Pharmaceutical R&D in March 2014

CHANG Xiaoshi1, WU Linping2

2014, 45(6): 4561-S62.

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