Chinese Journal of Pharmaceuticals

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Synthesis of Tofacitinib

ZHANG Zhongkui, KUANG Chunxiang*

2013, 44(4): 321-323.

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Tofacitinib, an anti-rheumatoid arthritis drug, was synthesized from N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(7) by removing the benzyl group and condensing with ethyl cyanoacetate in one-pot synthesis. The intermediate 7 could be obtained from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine(2) by protection, substitution and deprotection. The total yield of tofacitinib was about 57％(based on compound 2) with purity of 99.4％.

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Synthesis and Antibacterial Activity of 4''-Substituted Allyloxy Macrolide Derivatives

SHEN Shunyi, HUANG Xinyan, LIU Yubin, GE Han

2013, 44(4): 324-332.

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Twenty-one new substituted allyloxy macrolide derivatives were synthesized from azithromycin 11,12-cyclic borate and clarithromycin, respectively. The antibacterial activity of azithromycin 4''-substituted allyloxy, 3-decladinosyl-3-substituted allyloxy and 3-decladinosyl-3-substituted allyloxy 11,12-dimethoxyl derivatives were evaluated in vitro and compared. The results showed that introduction 4''-substituted allyloxy into azihtromycin improved antibacterial activity against tested Staphylococcus aureus, Enterococcus and Gamma streptococcus. Introduction 3-substituted allyloxy into azihtromycin reduced antibacterial activity and narrowed antimicrobial spectrum. Introduction 11,12-dimethoxyl futher reduced antibacterial activity. Heteroaryl substituted allyloxy derivatives exhibited better
antibacterial activities. In addition, introduction 3-O-[4-(2,5-dichlorophenoxy)-2-butenyl] into erythromycin A also reduced antibacterial activity and narrowed antimicrobial spectrum.

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Synthesis and Antibacterial Activity of Erythromycin A 6-O-Methyl-9-Substituted Azine Derivatives

GE Han, SHEN Shunyi

2013, 44(4): 333-336.

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Eighteen new erythromycin A 2'-O-acetyl-6-O-methyl-9-substituted azine and 6-O-methyl-9-substituted azine derivatives were synthesized from erythromycin thiocyanate. The antibacterial activities of the title compounds were evaluated in vitro and the results showed that most compounds exhibited good antibacterial activities against tested gram-positive microorganisms. These compounds were very active against gram-positive Staphylococcus epidermidis, Staphylococcus albus and Diplococcus lanceolatus.

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Directed Evolution of Cephalosporin C Acylase Activity by Error-prone PCR

WANG Yingqiu, ZHENG Linchong, XIE Liping, ZHU Baoquan, HU Youjia*

2013, 44(4): 344-347.

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In previous study, we obtained a cephalosporin C (CPC) acylase which could transform CPC to 7-aminocephalosporanic acid (7-ACA). Error-prone PCR was used to evolve this enzyme by adding different concentration of Mg2+ and Mn2+. The PCR product was cloned and transformed into E. coli.. More than 400 mutants were screened and 35 mutants showed increased activity. These improved mutants were purified by metal chelate affinity chromatography. After the secondary screening, one mutant showed significant elevated activity compared to the control and CPC conversion rate was enhanced approximately by 35％. The sequencing result showed that there were two point mutations in the mutate protein. The 122-alanine was substituted by valine. Further transformation research was conducted under the optimal conditions and the CPC conversion rate could reach 95％.

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Optimization of Decolorization Technology of Ganoderma sinense Polysaccharides by Response Surface Methodology

YANG Yuewen1, HU Xiao2, YANG Yifang2*, LUO Yongming1, LIAO Jianwei3

2013, 44(4): 348-351.

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Based on the Box-Behnken design principles, the method of response surface methodology with 3 factors and 3 levels was adopted on optimizing the resin decolorization technology of Ganoderma sinense polysaccharides. The factors influencing the technological parameters were determined by means of regression analysis. Response surface and contour were finally graphed with the decolorization rate as the response value. The optimal decolorization conditions were as follows: decolorization time of 2.5 h, 0.75 g/10 ml resin and temprature of 28 ℃. Under such conditions, the actual decolorization rate of Ganoderma sinense polysaccharides was 87.8％.

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Relationship between Swelling and Release Mechanism for Metformin Hydrochloride Sustained-release Tablets

ZHU Fangfang1,2, GAO Huisheng2, KULKARNI Anand2, HEGDE Deepak2, TU Jiasheng1*

2013, 44(4): 352-356.

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The formulation of the metformin hydrochloride (1) sustained-release matrix tablets with hydroxypropyl methylcellulose(HPMC) as matrix was optimized by orthogonal design. The results showed that the optimal tablets were prepared with HPMC K100M as matrix and polyvinylpyrrolidone (PVP) K90 as adhesive. The weight ratio of HPMC K100M to 1 was 0.25∶1. The swelling index and in vitro drug release of the product in different media (pH 1.0 HCl, pH 4.5 acetate buffer and pH 7.4 phosphate buffer) were determined. Four mathematical models were adopted to fit the experimental date to investigate the relationship between in vitro release and swelling
index. The results demonstrated that both the drug release and tablet swelling showed the best fitting with the Korsmeyer-Peppas model, the mechanism for controlling the drug release was the Fick diffusion. The drug release did not depend on the pH change of the medium. The swelling of the matrix played a leading role in the drug release process. There was a good linear relationship between drug release and matrix swelling.

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Preparation and in vitro Evaluation of Dutasteride Self-microemulsions

LIU Cui1, ZHANG Tao2,3, HUANG Hua1*, DING Yanji2,3, YI Zhonghong2,3

2013, 44(4): 357-361.

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Based on the results of the solubility test and pseudo-ternary phase diagrams, the components of a blank self-microemulsifying drug delivery system (SMEDDS) were obtained. The formulation was further optimized by central composite design combined with response surface methodology with particle size, ζ potential and in vitro dissolution of dutasteride as response variables. The optimal product was obtained by adding dutasteride into the blank SEMDDS consisting of caprylic monoglyceride, Cremophor EL and 1,2-propylene glycol with the weight ratio of 1∶1.46∶1.46. The dissolution behaviors of the product in four media (0.1 mol/L HCl, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and water) were similar. Compared with the commercial dutasteride soft capsules (Avodart), the dissolution of the SMEDDS was significantly improved. The results of the preliminary stability test showed that the product was rather stable.

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Preparation of Berberine Hydrochloride Microcapsules for Taste Masking by Fluidized Bed Coating

HU Xuelian1, HUANG Hua2, LI Yingbo2, WANG Xianzhu3

2013, 44(4): 362-365.

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The berberine hydrochloride powder was pre-granulated by fluidized bed tangential-spraying technology with 3％ hydroxypropyl methyl cellulose (HPMC) solution as adhesive to obtain the fine particles with the diameter of 75 - 150 μm. Then the above fine particles were coated with Eudragit E100 by fluidized bed bottom-spraying technology to obtain the title microcapsules with the coating level of 80％. The results showed that the diameter [d(0.5)] before and after bottom-spraying coating were 105 and 145 μm, respectively. The drug loading of the product without bitterness was 55％. The dissolution of the microcapsules at 30 min in 0.1 mol/L HCl was about 80％ while less than 1％ at 60 min in water. It indicated that the product could basically mask the bitter taste of the drug and rapidly release in 0.1 mol/L HCl so that the coating did not affect the absorption of the drug.

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In vitro Release and Pharmacokinetics of Sustained-release Tablets Loaded with Felodipine in Beagle Dogs

LIAO Hualin1, JI Jiebiao2, LI Jingyi1, HUANG Hua1*

2013, 44(4): 366-369.

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The felodipine sustained-release tablets A, B, C, D and E were prepared with the different particle size (D90) micronized bulk drug powder of 56.0, 41.8, 30.1, 14.3 and 6.9 μm, respectively. The in vitro release behaviors of the above self-made products and commercial sustained-release tablets (Plendil) in 1％ Tween-80 solution were investigated, respectively. The results showed that the f2 value between the product E and Plendil was 68.6. Further investigation carried out in five kinds of release medium: water, pH 1.2 HCl, pH 4.5 acetic acid-ammonium acetate buffer, pH 6.8 phosphate buffer and 0.5％ Tween-80 solution. The results showed that the in vitro release behavior of the product E was similar to Plendil owing to the f2 values were all over 50 in five media above. The pharmacokinetics of the two preparations in Beagle dogs were investigated. The main pharmacokinetic parameters of product E and Plendil were: tmax(2.5±0.5) and (3.2±0.4)h, cmax(56.9±2.0) and (53.2±6.6)ng/ml, t1/2 (5.7±2.2) and (4.9±1.6)h, AUC0→∞(263.4±15.1) and (261.6±38.1)ng·ml-1·h-1.

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Antitumor Effect of Sorafenib Combined with Itraconazole

WANG Juan, MA Shumei, CHEN Xiuhua

2013, 44(4): 370-375.

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The in vitro growth inhibition effects of sorafenib (1) combined with itraconazole (2) on A549 human lung adenocarcinoma cells, HCT116 human colon cancer cells and MDA-MB-435 human breast cancer cells were investigated. The A549 tumor bearing nude mouse models were adopted to evaluate the in vivo inhibition of the combined regimen. The effects on cell cycle, migration and vessel formation of the human umbilical vein endothelial cells (HUVEC) were also investigated at the cellular level. The inhibition on pulmonary metastasis of the combined regimen was tested with the mice bearing B16 melanoma as the animal models. The additive effects of 1 combined with 2 on the in vitro and in vivo inhibition of tumor cells were observed. The combination treatment could also inhibit the cell cycle progressionat the G0/G1 phase and inhibit the migration and vessel formation of HUVEC. The inhibition effect of the combination
on HUVEC was superior to 1 alone. The combination of sorafenib with itraconazole also displayed an additive effect on inhibition of pulmonary metastasis of B16 melanoma tumor.

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Determination of Eleven Components in Bushen Guchi Wan by LC-MS/MS Combined with Ion Switching Technology

ZHANG Zijian1, DONG Lihua2, SUN Dongxiao2, GUO Panpan2, WANG Chunying2*

2013, 44(4): 376-378.

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A LC-MS/MS method was established for the determination of eleven components in Bushen Guchi Wan. A C18 column was used with the mobile phase of methanol-water by gradient elution. Multiple reaction monitoring scanning mode was performed combined with the ion switching technology. Betaine, formononetin, schisandrin and 23-O-acetylalisol B were detected by positive ion scanning mode, while catalpol, sodium danshensu, salvianolic acid B, cinnamic acid, linarin, naringenin and paeonol were detected by negative ion scanning mode. All the compounds showed good linearity. Their recoveries were 98.5％ - 107.0％, with RSDs of 0.7％ - 3.1％.

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Isolation and Identification of An Unknown Impurity Contained in Ambroxol Hydrochloride Glucose Injection

LI Yuanyuan1, TIAN Yuan1, CHEN Dongjun1, WU Xiaoming2, ZHANG Zunjian1*

2013, 44(4): 379-382.

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An unknown impurity found in ambroxol hydrochloride glucose injection was isolated by UPLCDAD and identified by UPLC-IT-TOF-MS and NMR analysis. The structure was confirmed to be 4-(6,8-dibromo-3,4-dihydro-quinazolin-3-yl)cyclohexanol. The result could provide a basis for the quality assessment and sterilization process optimization of ambroxol hydrochloride glucose injection.

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Determination of Three Effective Components in Qing'e Pills by LC-MS/MS

MA Gaixia, JIA Yan, GUO Pengfei, HUANG Suzhen, SU Xiaojing

2013, 44(4): 382-385.

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A LC-MS/MS method was established for the determination of three components, pinoresinol diglucoside, psoralen and isopsoralen in Qing'e pills. A Kromasil C18 column was used with the mobile phase of methanol-0.1％ formic acid for gradient elution. ESI was applied with multiple reaction monitoring (MRM) scanning. The transitions of m/z 700.5→m/z 235.4 (pinoresinol diglucoside) and m/z 187.1→m/z 131.1 (psoralen and isopsoralen) were monitored. Their average recoveries were 99.1％, 99.0％ and 98.6％, with RSDs of 1.33％, 1.43％ and 1.27％.

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Determination of Sixteen Kinds of Phthalic Acid Esters Plasticizer in PVC Plastic

GU Haoqi1, MEI Lei1, WANG Jian2, ZHANG Yilan1*

2013, 44(4): 386-388.

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Sixteen phthalic acid esters as plasticizer in PVC plastic were extracted with hexane by ultrasonic extraction and detected by GC-MS method. The results showed that this method had a good linear correlation and the correlative coefficients were more than 0.999. Their low limits of detection were in the range of 0.5 - 1.5 mg/kg.

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Determination of Glucosamine Hydrochloride by UV Spectrophotometry of Cu2+ Complex

XUE Jiyang, WANG Yaping, ZHANG Yaoshu*

2013, 44(4): 389-391.

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An UV method was established for the determination of glucosamine hydrochloride. In alkaline solution, glucosamine hydrochloride reacted with Cu2+ to form a stable complex which had a specific absorption wavelength in ultraviolet region. The absorption spectrum of this complex showed a well-defined absorbance maximum at 237 nm. The calibration curve was linear in the range of 0.03 - 0.055 mg/ml. The average recovery was 100.1％, with RSD of 0.57％.

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Progress in Design and Performance Evaluation of Aerosolization Channel for Dry Powder Inhaler

HENG Ruilin, CHEN Lan*, SI Guoning, LIU Yang

2013, 44(4): 392-398.

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With the development of technology and pharmaceutical engineering, dry powder inhalers (DPI) are becoming the important means of effective therapy for pulmonary disease. Because of the advantages of this treating method, the clinical applications have increased year by year. Aerosolization channel for the depolymerization, atomization and transportation of the active ingredient is an important structure unit of DPI which directly affects the treatment effect. The structures and principles of different kinds of aerosolization channel, the numerical simulation techniques for the design of aerosolization channel, and the performance evaluation methods are reviewed in this paper.

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Graphical Synthetic Routes of Telaprevir

XUE Yan, WANG Zhefeng, ZHONG Jingfen*

2013, 44(4): 404-407.

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Multiple Dissolution Profiles, the Agreement Evaluation Technology of Oral Solid Dosage Forms of Generic Drug

XIE Mufeng

2013, 44(4): 411-414.

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