主办：上海医药工业研究院
　　　中国药学会
　　　中国化学制药工业协会
ISSN 1001-8255   CN 31-1243/R   ZYGZEA
Chinese Journal of Pharmaceuticals

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    Perspectives & Review
  • Perspectives & Review
    Research Progress of Immobilized Ketoreductase in Continuous Flow Synthesis
    HU Pan , WU Xiaofan, HUANG Zedu, CHEN Fener,
    2025, 56(4): 421. https://doi.org/10.16522/j.cnki.cjph.2025.04.001
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    As environmentally benign and sustainable technologies, enzyme immobilization and continuous flow synthesis have been widely applied to organic synthesis. In recent years, immobilized enzyme based flow biocatalysis has received increasing attention and application, because it possesses the integrated advantages of the both. Ketoreductasecatalyzed asymmetric reduction of prochiral ketones is one of the most effective methods for the synthesis of chiral alcohols. This paper summarizes the research progress of immobilized ketoreductase in continuous flow synthesis, and provides certain reference for developing efficient, economic, and sustainable flow biocatalysis approaches.
  • Perspectives & Review
    Research Progress of Droplet-based Microfluidic Technology in the Preparation of Microspheres
    SHI Limin, ZHU Chunmei, HUANG Jin, CHEN Jinmin, ZHANG Fuli, WU Haoxiang
    2025, 56(4): 435. https://doi.org/10.16522/j.cnki.cjph.2025.04.002
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    Droplet-based microfluidic technology shows great application potential in the preparation of drug delivery systems due to its excellent handling of fluids at the micro- or nano-scale. Compared with the microspheres prepared by conventional preparation methods, the microspheres prepared by droplet-based microfluidics exhibit a welldefined and controllable composition and structure, high monodispersity, and good process reproducibility. Focusing on the droplet generation passive method and passive microchannel device, this review introduces the basic principles of microsphere preparation by droplet -based microfluidics, and systematically analyzes the main effects of fluid-related parameters, device design parameters and additives on the critical quality attributes, including microsphere morphology, particle size distribution, encapsulation efficiency, and drug release behavior. It is hoped that this review can provide a reference for the research and development of microspheres.
  • Perspectives & Review
    Research Progress on Permeation Enhancers Derived from Traditional Chinese Medicines to Promote Oral Absorption of Drugs
    JIANG Yutong , SHENG Jianyong, CHEN Mingwei , WANG Jianxin , LI Xilin
    2025, 56(4): 444. https://doi.org/10.16522/j.cnki.cjph.2025.04.003
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    Permeation enhancers can enhance the penetration ability of active pharmaceutical ingredients through the epithelial cell layer of the gastrointestinal tract, which is an important strategy to enhance oral absorption efficiency. Permeation enhancers derived from traditional Chinese medicines often have a long history of human use, with good biocompatibility and manageable adverse reactions. This review provides an overview of the intestinal epithelial barrier to oral absorption of drugs and highlights the research progress of traditional Chinese medicine-derived permeation enhancers in promoting the oral absorption of small molecule drugs, macromolecular drugs, and nanomedicines by overcome this barrier. This review also summarizes the absorption promotion effects and mechanisms of traditional Chinese medicinederived permeation enhancers on the above drugs, aiming to provide literature support for further exploration and in-depth research on traditional Chinese medicine-derived permeation enhancers.
    • Paper
  • Paper
    Synthesis Process Improvement of Carboprost Methylate
    ZHANG Xiaoyan, WU Xuesong , TANG Zhiwei , SI Weidong , WANG Shouxin , WANG Hongbo
    2025, 56(4): 451. https://doi.org/10.16522/j.cnki.cjph.2025.04.004
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    The existing synthesis route of carboprost methylate(1) was optimized. A seven step synthetic route was designed using (–)-Corey lactone 4-phenylbenzoate(2) as the starting material, which involved selective oxidation of 2 with 2,2,6,6-tetramethylpiperidinyl-1-oxide(TEMPO)/NaClO, followed by Wittig-Horner reaction, Grignard reaction, reduction, Wittig reaction, esterification, and deprotection of the 4-phenylbenzoyl group. The chiral isomers were then separated by column chromatography to yield the target compound 1, with the total yield of 10.53% and the purity of 99.2%. The optimized route minimized the risk of protecting group loss and hydroxyl group elimination. Notably, the purification step by column chromatography in the initial five stages was eliminated. The chiral isomers were effectively purified with only two times of column chromatography first reported, which greatly reduced the cost of separation and purification. This paper aimed to provide some references for the industrial production of 1 and carboprost tromethamine.
  • Paper
    New Preparation Process of Cenobamate
    YU Zenghui, WANG Hui, LU Tianyu, YANG Xiangping, XU Xiangyang
    2025, 56(4): 457. https://doi.org/10.16522/j.cnki.cjph.2025.04.005
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    The synthetic process of cenobamate(1) had been improved in this paper. Using 1-(2-chlorophenyl)- ethan-1-one(7) as raw material, 2-bromo-1-(2-chlorophenyl)ethan-1-one(2) was prepared with N-bromosuccinimide. Then, 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethane-1-one(8) was prepared by condensation of 2 and 1H-tetrazole. After ketoreductase reduction of compound 8, (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethane-1-ol(5) was generated. Compound 5 reacted with N,N-carbonyldiimidazole and concentrated ammonium hydroxide to prepare the target compound 1, with the purity of 99.9％ and the ee value of 99.9％ . This optimized synthetic route used self-developed ketoreductase to synthesize the single configuration of 5, which had low production cost, high reduction selectivity, and no need for resolution, conforming to the principles of green chemistry.
  • Paper
    Synthesis of Related Substances of Relugolix
    WANG Haibo, FENG Zhong, ZHENG Jiafang, XUN Mingjin, ZHANG Guimin
    2025, 56(4): 463. https://doi.org/10.16522/j.cnki.cjph.2025.04.006
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    To control the quality of relugolix(1), four process impurities were synthesized, namely 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)- thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (related substance A), 1-[4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)- methyl]-2,4-dioxo-3-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]- phenyl]-3-methoxyurea(related substance B), 1,3-bis[4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6- methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl]urea (related substance C) and 1,5-bis[4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxy biuret (related substance D). The related substances A and B were reported at the first time. This article aimed to provide the reference substances for the quality research of 1, and also to offer the insights for further optimization of the synthetic process of 1.
  • Paper
    Design, Preparation and Evaluation of Novel Organic Acid-colistin E2 Complexes
    MEI Haoran , LI Yanan , LU Jianguang, DONG Yuanzhen, ZHANG Ying , FENG Jun,
    2025, 56(4): 469. https://doi.org/10.16522/j.cnki.cjph.2025.04.007
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Multidrug-resistant(MDR) Gram-negative bacterial infections pose a growing global health threat. Although polymyxins remain the last-line therapy, the nephrotoxicity severely limits their clinical utility. This study developed reversible anionic complexes of colistin E2 with linear/cyclic organic acids to mitigate toxicity while retaining efficacy. Organic acids were synthesized via Fmoc solid-phase synthesis and formed complexes with colistin E2 through anion exchange, as confirmed by ion chromatography. Among them, the complex of colistin E2 and OA-12 demonstrated potent antimicrobial activity(MIC=0.5 – 1 μg/mL) against Gram-negative bacteria without cytotoxicity in normal rat kidney cells(NRK-52E cells). In vivo toxicity evaluation revealed no increased acute toxicity in mice, but reductions in nephrotoxicity biomarkers. Compared with the mice in the colistin E2 treatment group, the serum creatinine, blood urea nitrogen, 7-day neutrophil gelatinase-associated lipocalin(NGAL), 14-day NGAL, and urinary kidney injury molecule 1(KIM-1) levels in the complex-treated mice decreased by 1.43％ , 16.00％ , 25.47％ , 16.31％ , and 14.56％ , respectively. In summary, this study proposes a novel prodrug strategy via anion complexation, providing a promising approach to enhance the safety profile of polymyxins while maintaining therapeutic efficacy against MDR infections.
  • Paper
    In vitro Permeation Test of Progesterone Vaginal Sustained-release Gel through Porcine Vaginal Mucosa and Skin
    XIAO Cenyu, SU Wenjun, ZHANG Rong , LI Yajuan , GAO Xiaoli,
    2025, 56(4): 480. https://doi.org/10.16522/j.cnki.cjph.2025.04.008
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    An in vitro permeation test(IVPT) method for progesterone vaginal sustained-release gel was established and used to evaluate the permeability differences of the commercially available preparation Crinone® in excised porcine vaginal mucosa and skin of Bama miniature pigs. Franz diffusion cell was used for the IVPT, and an established HPLC method was employed to detect the concentration of progesterone in the receiving medium. Then, the cumulative permeation amounts and average permeation rates of progesterone were calculated in both of the tests. The results showed that the IVPT method had good precision, accuracy, and discrimination. The 24 h cumulative permeation amounts of the progesterone vaginal sustained-release gel through the excised porcine vaginal mucosa and Bama miniature pig skin were (187.23±11.39) and (35.50±4.80)μg/cm2 , respectively. The results of IVPT showed that compared with Bama miniature pig skin, the progesterone vaginal sustained-release gel exhibited stronger permeability on excised porcine vaginal mucosa. Furthermore, the in vitro release test results showed that the cumulative release rate data of the commercially available preparation fit well with the Ritger-Peppas model.
  • Paper
    Investigation on Physicochemical Properties and in vitro Pharmacodynamic Evaluation of Transferrin-modified Enzyme-sensitive Nanomicelles Co-loaded with Sorafenib and Bakuchiol
    ZOU Naijian , KONG Liang , CHANG Lei , LU Yingqiang
    2025, 56(4): 488. https://doi.org/10.16522/j.cnki.cjph.2025.04.009
    Abstract ( ) Download PDF ( )   Knowledge map   Save
    Renal cell carcinoma exhibits extremely high inter- and intra-tumor heterogeneity, which has led to unsatisfactory therapeutic outcomes for chemotherapeutic agents. In recent years, the combination of multi-target drugs and nanocarrier systems has shown tremendous potential in inhibiting the growth and metastasis of malignant tumors. This study focused on the highly expressed matrix metalloproteinase-2(MMP-2) in the tumor microenvironment and employed the film dispersion method to construct novel MMP-2-responsive nanomicelles co-loading sorafenib and bakuchiol. The research systematically investigated the synergistic effects of sorafenib and bakuchiol, optimized the drug ratio, evaluated the physicochemical properties of the nanomicelles, and assessed their ability to inhibit the growth and metastasis of renal cancer cells in vitro. Results demonstrated that the nanomicelles enhanced drug targeting and stability through a dual-targeting strategy combining passive targeting via the EPR effect and transferrin receptor-mediated endocytosis, effectively reduced drug dosage and toxicity. The nanomicelles exhibited strong inhibitory effects on the growth, invasion, and metastasis of tumor cells, offering a new approach and strategy for targeted therapy in renal cell carcinoma and other malignant tumors.
  • Paper
    Optimization of the Formulation of Telmisartan Capsules by Orthogonal Design Combined with Entropy Weight Method and the Pilot Scale-up Study
    YAN Meijiao , ZHANG Qinghua , WANG Leyun,
    2025, 56(4): 500. https://doi.org/10.16522/j.cnki.cjph.2025.04.010
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    Telmisartan granules were prepared using a fluidized bed method, and then filled into capsules. The formulation of above capsules was optimized by orthogonal design with bulk density and Carr index of the granules and similarity factor of the dissolution curves between the self-made capsules and the reference listed drug(RLD) as indicators. The comprehensive evaluation based on the entropy weight method revealed that the order of influence on the overall score was as follows: carbomer dosage > ratio of mannitol to microcrystalline cellulose > meglumine dosage > magnesium stearate dosage. The final optimal formulation consisted of 1.2％ of carbomer, 5％ of meglumine, the 2∶1 ratio of mannitol to microcrystalline cellulose, and 0.25％ of magnesium stearate. Subsequently, scale-up trials were conducted for 100 000 and 500 000 capsules using the optimal formulation, and the pilot-scale samples were compared with small-scale samples and the reference drug. The results indicated that the key quality attributes of the pilot-scale samples met production requirements. This optimal formulation derived from this study was stable, reliable, easy to operate, and exhibits remarkable consistency in dissolution profiles. These findings establish a solid scientific basis for large-scale production of telmisartan capsules.
  • Paper
    Investigation of the Thermo-oxidative Degradation of Polidocanol by Chromatography, NMR and Mass Spectrometry
    MA Yiwen, LI Xiaoguang, JIA Youzhi, PAN Hongjuan
    2025, 56(4): 505. https://doi.org/10.16522/j.cnki.cjph.2025.04.011
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    To investigate the thermal oxidative degradation pathway of polidocanol(1), a destructive test was conducted in a thermo-oxidative environment of 60 ℃ to analyze the changes in its component distribution and degradation product content. The nuclear magnetic resonance spectroscopy was used to analyze the structure of degradation products, and liquid chromatography/electrostatic field orbital trap mass spectrometry was employed to assign the degradation products. The results showed that 12 non-volatile degradation products could be generated under thermooxidative conditions. Besides polyethylene glycol, the main degradation products were inferred as an alkoxyformate, three polyethylene glycol analogs, formates, hemiacetals, hydroperoxides, and several in-chain esters. Moreover, a possible thermo-oxidative degradation pathway of 1 was proposed, along with factors influencing the degradation. The results lay a foundation for impurity research on 1 and provide a reference for improving its manufacturing process, storage and specification.
  • Paper
    Research on Sterility Test Method of Wound Dressing Containing Tea Tree Oil and Carbomer
    FAN Lanyan , TENG Yonghui , LI Xueling , GAN Yongqi , ZHU Bin
    2025, 56(4): 519. https://doi.org/10.16522/j.cnki.cjph.2025.04.012
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    A sterility test method for wound dressing containing tea tree oil was established. A sterile pH 6.8 phosphate buffer solution containing 0.1 mol/L calcium chloride was used to break the gel of carbomer in wound dressings, and the antibacterial activity of the wound dressings was removed by membrane filtration. Add the test sample(equivalent to 0.5 g of the wound dressing) to 50 mL of sterile 0.9％ sodium chloride solution. Rinse with sterile 0.9％ sodium chloride solution containing 0.3％ polysorbate 80(rinsing volume per membrane ≥ 300 mL), and inject culture medium containing 1％ polysorbate 80. The established method could eliminate both the interference of carbomer and the antibacterial activity of the wound dressing. Six strains of test bacteria in the experimental group grew well compared with the positive control group, meeting the requirements of Part Ⅳ(General Rule 1101) of the ChP 2020 edition, which provided a reference for sterile testing of medical devices containing antibacterial ingredients and carbomers.
  • Paper
    Determination of Four Aflatoxins in Fermented Drugs by Liquid-liquid Extraction-HPLC-MS/MS
    WU Chunyan, YANG Heyou , XU Haiju , SHAO Wujun, HE Yanling
    2025, 56(4): 525. https://doi.org/10.16522/j.cnki.cjph.2025.04.013
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    A liquid-liquid extraction-high performance liquid chromatography triple quadrupole mass spectrometry(HPLC-MS/MS) method was established to analyze the residual levels of four aflatoxins(AF), namely AFB1, AFB2, AFG1, and AFG2, in the fermented drugs. The sample was dissolved in water and extracted with dichloromethane, and then concentrated by nitrogen blowing and dissolved in 30％ methanol. Finally, it was detected by the HPLC-MS/MS method. The results showed that it was linear for four AFs in the range of 0.10 - 10 ng/L, with a detection limit of 0.03 μg/kg and a quantification limit of 0.1 μg/kg. In the fermented drug matrix, the spiked recovery rate of AFs was 80％ - 105％ , with the RSD of 0.2％ - 5％ . The sample testing results showed that AF was not detected in any of the 8 fermented drugs. The established method is simple, sensitive, and highly accurate, which can quantitatively detect AF and provide strong technical support for the quality control of fermented drugs and AF contamination control.
  • Paper
    Determination of Sulfates as Genotoxic Impurities in Sildenafil Citrate
    LI Cuifen, QIAN Ribin, LI Jianhua, QIN Fei,
    2025, 56(4): 531. https://doi.org/10.16522/j.cnki.cjph.2025.04.014
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    The detection methods were established for diethyl sulfate(2) and ethyl hydrogen sulphate(3) as the genotoxic impurities in sildenafil citrate(1). Compound 2 was determined by GC-MS method with TG-5SILMS capillary column(30 m×0.25 mm×0.25 μm) as the chromatographic column, helium as the carrier gas, and selected ion monitoring(SIM) mode for determination. Compound 3 was determined by LC-MS/MS method with an Agilent Zorbax C18-AQ Plus column (4.6 mm×100 mm, 3.5 μm). And the analysis was carried out in the gradient elution mode with 0.1％ formic acid solution containing 50 mmol/L ammonium formate as mobile phase A, and methanol as mobile phase B. The electrospray ionization(ESI) source and multi reaction monitoring(MRM) mode were adopted. The results showed that it was linear for 2 and 3 in the ranges of 21.1 - 422.6 and 4.06 - 81.2 ng/mL, respectively. The average recovery rates(n=9) of 2 and 3 were 104.6％ and 104.8％ , respectively, with detection limits of 7.04 and 2.03 ng/mL, and quantification limits of 21.1 and 4.06 ng/mL, respectively. The established method is accurate, sensitive, and convenient, which can be used for the determination of 2 and 3 in 1.
  • Paper
    Determination of 8 Elemental Impurities in Tenofovir Alafenamide Fumarate by ICP-MS
    LI Yalei, LI Yuehua, HAN Fei
    2025, 56(4): 536. https://doi.org/10.16522/j.cnki.cjph.2025.04.015
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    An inductively coupled plasma mass spectrometry(ICP-MS) method was established to determine 8 elemental impurities, namely Pb, V, As, Hg, Cd, Co, Ni, and Cr, in tenofovir alafenamide fumarate(1). The sample was dissolved and diluted with an internal standard solution(containing Bi, Y, In, and Sc elements). Then, the sample was directly injected into the ICP-MS system. The results showed that it was linear for the 8 elements in the corresponding concentration ranges. The detection limits were 0.21 - 7.69 μg/kg, and the quantification limits were 0.71 - 25.60 μg/kg. The sample recovery rates(n=9) were 93.41％ - 108.88％ , the RSDs(n=6) of the repeatability test were 0.64％ - 1.56％ . The solution had good stability within 2 hours at room temperature. The content of each element impurity in multiple batches of samples was far below its limit value. The established method has good specificity, high sensitivity, and good accuracy and precision, which can meet the quality control of element impurities in 1.
  • Paper
    Determination of Four Volatile Impurities in Octoxynol 40 by Head-space Gas Chromatography
    LYU Bo, JIANG Zhenzhen , DU Kunyu, REN Huixu, HE Fei, LIU Yiqing
    2025, 56(4): 541. https://doi.org/10.16522/j.cnki.cjph.2025.04.016
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    A headspace gas chromatography(HS-GC) method was established to determine the contents of four impurities, namely acetaldehyde, formaldehyde, ethylene oxide, and dioxane, in octylphenol polyoxyethylene ether 40(OP- 40). The standard addition method was employed for the analysis. The sample was dispersed with water as the solvent, and equilibrate at 70 ℃ for 30 min in the headspace chamber. A hydrogen flame ionization detector(FID) was used, and a capillary column(60 m×0.25 mm×1.4 μm) was employed for measurement at programmed temperature. The results showed that under the proposed chromatographic conditions, the 4 compounds were well separated, and it was linear for the four impurities in the range of 0.05 - 21.56 μg/g. The detection limits were 0.02 - 0.32 μg/g. The average recovery rates(n=9) of acetaldehyde, formaldehyde, ethylene oxide, and dioxane were 103.3 ％ , 99.8 ％ , 99.1 ％ and 100.1 ％ , respectively. The established method is applicable for the daily detection of four impurities in OP-40, which provides a reference for improving its quality specification
    • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    Production and Process Concerns Regarding Prophylactic mRNA Vaccines
    YU Jianing, LIU Fen
    2025, 56(4): 547. https://doi.org/10.16522/j.cnki.cjph.2025.04.017
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  • Pharmaceutical Management & Information
    Discussion on the MAH’s Quality System in the Case of Contract Cooperative Manufacturing of Biological Products
    CAO Meng, CHENG Yin, WANG Jiajing, DONG Zhenglong, LI Xiangyu
    2025, 56(4): 552. https://doi.org/10.16522/j.cnki.cjph.2025.04.018
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  • Pharmaceutical Management & Information
    Contamination Risk and Sterilization Method of the Pharmaceutical Water Storage and Distribution System
    WU Yu, YU Bowen, ZHAO Xingping, CHEN Fuchao, YANG Lei
    2025, 56(4): 559. https://doi.org/10.16522/j.cnki.cjph.2025.04.019
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  • Pharmaceutical Management & Information
    Twelve Principles of Green Chemistry in Pharmaceutical Manufacturing
    The Academic Committee of the th Mogan Mountain International Conference on Green Pharmaceuticals
    2025, 56(4): 564. https://doi.org/10.16522/j.cnki.cjph.2025.04.020
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