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成果及论文

代表性研究成果

案例一:瑞戈菲尼(REG)是一种口服多激酶抑制剂,用于治疗胃肠道间质瘤、转移性结直肠癌和晚期肝细胞癌。REG水溶性低,目前以其一水合物形式(REG·H2O)上市,化合物专利于2024年到期,晶型专利于2027年到期。为提高REG水溶性,丰富REG固体形式,突破其晶型专利壁垒,本研究合成了REG与丙二酸(REG–MA)、戊二酸(REG–GA)和庚二酸(REG–PA)的三种共晶,对其进行了全面的固态表征。与商用晶型相比,REG–GAREG–PA具有显著提高的表观溶解度和溶解速率,同时不影响药物的吸湿性和物理化学稳定性。此外,共晶的形成也改善了REG的可压片性。表明REG–GAREG–PA具有较大的潜力用于REG改良型制剂的开发。(CrystEngComm 2021, 23, 653–662. DOI: 10.1039/d0ce01341b

案例二:维罗非尼(VEM)是一种选择性的BRAF V600激酶抑制剂,临床上用于治疗具有BRAF V600突变阳性的发生转移或不可切除的黑色素瘤。VEM难溶于水,目前以无定形固体分散体形式上市,其化合物专利于2024年到期,晶型专利于2030年到期。为开发水溶性更高、稳定性更好的固体形式,本研究制备了VEMD-樟脑磺酸(D-CSA),L-樟脑磺酸(L-CSA)及DL-樟脑磺酸(DL-CSA)的三个盐。结果表明,三种盐型的吸湿性、稳定性、可压片性均优于无定形VEM;且大鼠体内的口服吸收远远优于无定形VEM,盐型中维罗非尼的CmaxAUC值分别比无定形提高了9倍和4倍左右。这可能是由于无定形的VEM在体内结晶,而樟脑磺酸盐在体内保持稳定的晶相所致。这一工作为开发具有更好的体内外性质的VEM改良型制剂提供了研究基础。(Journal of Drug Delivery Science and Technology 2022, 70, 103230. DOI: 10.1016/j.jddst.2022.103230

案例三:利巴韦林(RBV)是一种广谱抗病毒药物,溶解度高(140 mg/mL),剂量大(800-1200 mg/日),血药浓度峰谷效应和不良反应较严重。为了降低药物的溶解度和溶解速率,减缓药物释放,从而降低峰谷效应和不良反应,本研究制备了利巴韦林与溶解度相对较低的3,5-二羟基苯甲酸、没食子酸、巴比妥酸形成的三个共晶。体外释放曲线显示,形成共晶有效降低了药物的释放速率,特别是3,5-二羟基苯甲酸形成了氢键框架结构来包结药物,其释放速率降低最为明显。研究表明,与溶解度相对较低的共晶配体形成共晶是延缓药物释放的有效策略。(Cryst. Growth Des. 2014, 12, 63996408. DOI: 10.1021/cg501247x

案例四:阿昔洛韦是一种嘌呤核苷类似物,用于治疗单纯疱疹病毒感染,药用晶型为其2/3水合物(ACV·2/3H2O)。阿昔洛韦是一种BCS IV类药,溶解度低(约1.6 mg/mL),渗透性差(log P = 1.56),导致经皮吸收受限。本研究制备了阿昔洛韦与马来酸的盐,以及与富马酸和戊二酸的两种共晶。体外溶出和经大鼠皮肤的渗透性评价显示,与药用晶型相比,盐和共晶的最大表观溶解度均有显著提高;阿昔洛韦与富马酸和戊二酸共晶的累计渗透量和渗透速率有明显改善,而马来酸盐的渗透性有所降低。表明形成共晶可同时改善药物的水溶性和经皮渗透性。(CrystEngComm 2013, 15, 6457–6460. DOI: 10.1039/c3ce41017j

案例五:阿德福韦酯(AD)是一种核苷酸类似物,用于治疗慢性乙肝。AD易降解,化学稳定性差,其降解路径包括磷酸酯水解和腺嘌呤基团聚合。为提高其稳定性,本研究制备了AD与没食子酸的共晶,以及与水杨酸和马来酸的盐。动态水分吸附实验显示,AD70% RH下逐渐吸水转晶形成其二水合物,而共晶和盐在高湿度下保持稳定。在加速稳定性实验条件下,AD原料药逐渐降解,6个月后药物含量仅为93%;形成共晶或盐后,其降解过程得到明显抑制,6个月后的药物含量仍超过98%。为进一步考察共结晶分别对水解和聚合过程的影响,将样品置于60 °C/75% RH条件下,发现3天后AD原料药有27%发生水解,有51%发生聚合,而共晶和盐的水解和聚合过程均受到显著抑制,表现出显著改善的稳定性。结合晶体结构分析,提出AD稳定性提高的相关机制:AD与配体共结晶形成了稳定的异元氢键超分子合成子,同时相邻的药物分子被共晶配体隔开,能够同时抑制AD的水解和聚合反应。(Eur. J. Pharm. Sci. 2016, 85, 141–148. DOI: 10.1016/j.ejps.2015.10.006

案例六:替莫唑胺(TMZ)是治疗恶性胶质细胞瘤的一线药物,具有体内消除快,口服半衰期短,稳定性差和压片性能差等问题。黄芩素(BAI)具有显著的抗胶质瘤活性及良好的血脑屏障通透性,但水溶性差(16.0 μg/mL),口服生物利用度低。为克服传统复方药物均一性差、稳定性差、制剂相容性差的问题,并同时优化两种药物理化性质,本研究制备了替莫唑胺与黄芩素的药物-药物共晶。研究表明,形成共晶后,替莫唑胺的物理化学稳定性和压片性均得到显著改善;黄芩素的最大溶解度提高到原料药的25倍以上,而替莫唑胺的溶解度降低至原料药的1/10左右,极大地减小了二者的溶解度差异,改善了制剂相容性。大鼠口服药动学实验显示,形成共晶后,黄芩素的最大血药浓度及口服生物利用度显著增加;替莫唑胺的口服半衰期延长至原料药的2.6倍,说明其在病灶处的作用时间可能会相应地延长。因此,替莫唑胺-黄芩素共晶有望开发为一种克服传统复方药物的固有缺陷,且理化性质和药动学性质明显优于各原料药的改良型复方制剂。(Cryst. Growth Des. 2018, 18, 4270–4274. DOI: 10.1021/acs.cgd.8b00807

学术论文

1. X. X. Liu, P. Shi, X. L. Dai, Y. L. Huang, T. B. Lu, J. M. Chen*, Photophysics of charge transfer cocrystals composed of fluorene and its heterocyclic analogues as donors and TCNQ as an acceptor, CrystEngComm, 2022.

2. C. Wu, L. Gao, J. Xiong, X. L. Dai*, W. Gao, T. B. Lu, J. M. Chen*, Salts of rucaparib with dicarboxylic acids: synthesis, crystal structures and solubility aspects, CrystEngComm, 2022, 24, 7813-7820.

3. B. Y. Ren, X. L. Dai, F. Zhang, X. Long, Y. L. Huang, J. M. Chen*, T. B. Lu, “Drug-Coformer-Drug” Multicomponent Crystals to Simultaneously Improve the Solubility of Two Insoluble Combined Drugs by Introduction of a Soluble Coformer, Crystal Growth & Design, 2022, 22(10), 5785-5790. 

4. Pan Shi, Xiao-Xu Liu, Xia-Lin Dai, Tong-Bu Lu, Jia-Mei Chen*. Near-infrared Photothermal Conversion Properties of Carbazole-based Cocrystals with Different Degrees of Charge Transfer. CrystEngComm, 2022, 24, 4622-4628.

5. Guan-Lan Huang, Ling Yang, Bo-Ying. Ren, Xin-Yue Lv, Ling-Yi Song, Xia-Lin Dai*, Jia-Mei Chen*. Simultaneously Improving the Physicochemical and Pharmacokinetic Properties of Vemurafenib through Cocrystallization Strategy. Journal of Drug Delivery Science and Technology, 2022, 70, 1773-2247.

6. Bo-Ying Ren, Xia-Lin Dai, Jia-Mei Chen*, Tong-Bu. Lu. Two Anhydrous forms and Ane Monohydrate of a Cocrystal of Axitinib and Glutaric Acid: Characterization, Property Evaluation and Phase Transition Study. CrystEngComm, 2022, 24(11), 2138-2148.

7. Bo-Ying Ren, Xia-Lin Dai*, Jie Wang, Chao Wu, Tong-Bu Lu, Jia-Mei Chen*. Cocrystallization of Axitinib with Carboxylic Acids: Preparation, Crystal Structures and Dissolution Behavior. CrystEngComm, 2021, 23, 5504-5515.

8. Jie Wang, Xia-Lin Dai*, Tong-Bu Lu, Jia-Mei Chen*. Temozolomide–Hesperetin Drug–Drug Cocrystal with Optimized Performance in Stability, Dissolution, and Tabletability. Crystal Growth & Design, 2021, 21(2), 838-846.

9. Jun-Long Jia, Xia-Lin Dai, Hao-Jie Che, Meng-Ting Li, Xiao-Mei Zhuang, Tong-Bu Lu , Jia-Mei Chen*. Cocrystals of Regorafenib with Dicarboxylic Acids: Synthesis, Characterization and Property Evaluation. CrystEngComm, 2021, 23, 653-662.

10. Wen-Ting Lv, Xiao-Xu Liu, Xia-Lin Dai, Xiang-Tian Long, Jia-Mei Chen*. A 5-fluorouracil-kaempferol Drug-drug Cocrystal: Ternary Phase Diagram, Characterization and Property Evaluation. CrystEngComm, 2020, 22, 8127-8135.

11. Qian-Qian Hao, Xia-Lin Dai, Yong-Liang Huang, Jia-Mei Chen*, Tong-Bu Lu. Modulation of Solid-State Optical Properties of o-Hydroxynaphthoic Acids through Formation of Charge Transfer Cocrystals with TCNB. Crystal Growth & Design, 2020, 20(11), 7492-7500.

12. Xia-Lin Dai, Jia Yao, Chao Wu, Jun-Hui Deng, Yong-Hui Mo, Tong-Bu Lu, Jia-Mei Chen*. Solubility and Permeability Improvement of Allopurinol by Cocrystallizaiton. Crystal Growth & Design, 2020, 20(8), 5160-5168.

13. Zhao-Jun Yuan, Xia-Lin Dai, Yong-Liang Huang, Tong-Bu Lu, and Jia-Mei Chen*. Cocrystals of Penciclovir with Hydroxybenzoic Acids: Synthesis, Crystal Structures, and Physicochemical Evaluation. Crystal Growth & Design, 2020, 20(6), 4108-4119.

14. Xia-Lin Dai, Chao Wu , Jin-Hui Li, Lian-Chao Liu, Xin He, Tong-Bu Lu*, Jia-Mei Chen*. Modulating the Solubility and Pharmacokinetic Properties of 5-fluorouracil via Cocrystallization. CrystEngComm, 2020, 22(21), 3670-3682.

15. Yan Yan, Xia-Lin Dai, Jun-Long Jia, Xing-Hua Zhao, Zhi-Wei Li, Tong-Bu Lu, Jia-Mei Chen*. Crystal Structures, Stability, and Solubility Evaluation of Two Polymorphs of a 2:1 Melatonin–Piperazine Cocrystal. Crystal Growth & Design, 2020, 20(2), 1079-1087.

16. Xia-Lin Dai, Alexander P. Voronin, Yong-Liang Huang, German L. Perlovich, Xing-Hua Zhao, Tong-Bu Lu, Jia-Mei Chen*. 5-Fluorouracil Cocrystals with Lipophilic Hydroxy-2-Naphthoic Acids: Crystal Structures, Theoretical Computations, and Permeation Studies. Crystal Growth & Design, 2020, 20(2), 923-933.

17. Qian Tao, Qian-Qian Hao, Alexander P. Voronin, Xia-Lin Dai, Yu Huang, German L. Perlovich, Tong-Bu Lu*, Jia-Mei Chen*. Polymorphic Forms of a Molecular Salt of Phenazopyridine with 3,5-Dihydroxybenzoic Acid: Crystal Structures, Theoretical Calculations, Thermodynamic Stability, and Solubility Aspects. Crystal Growth & Design, 2019, 19(10), 5636-5647.

18. Xia-Lin Dai, Alexander P. Voronin, Wei Gao, German L. Perlovich, Tong-Bu Lu, Jia-Mei Chen*. Intermolecular Interactions and Permeability of 5-fluorouracil Cocrystals with a series of Isomeric Hydroxybenzoic Acids: a Combined Theoretical and Experimental Study. CrystEngComm, 2019, 21(34), 5095-5105.

19. Qi Lu, Jiang-nan Dun, Jia-Mei Chen, Shu-yu Liu*, Changquan Calvin Sun*. Improving Solid-State Properties of Berberine Chloride through Forming a Salt Cocrystal with Citric Acid. International Journal of Pharmaceutics, 2019, 554, 14-20.

20. Yu-miao Luo, Si-qi Chen, Jian-le Zhou, Jia-mei Chen, Li-wenTian, Wei Gao, Ying-yi Zhang, An-de Ma, Liang Li*, Zheng-zheng Zhou*. Luteolin cocrystals: Characterization, evaluation of solubility, oral bioavailability and theoretical calculation. Journal of Drug Delivery Science and Technology, 2019, 50, 248-254.

21. Jin-Mei Li, Xia-Lin Dai, Gao-Jie Li, Tong-Bu Lu, and Jia-Mei Chen*. Constructing Anti-Glioma Drug Combination with Optimized Properties through Cocrystallization. Crystal Growth & Design, 2018, 18(8), 4270-4274.

22. Xia-Lin Dai, Jia-Mei Chen*, Tong-Bu Lu*. Pharmaceutical Cocrystallization: an Effective Approach to Modulate the Physicochemical Properties of Solid-State Drugs. CrystEngComm, 2018, 20(36), 5292-5316.

23. Yu Huang, Jin-Mei Li, Zhi-Hui Lai, Jun Wu, Tong-Bu Lu, Jia-Mei Chen*. Phenazopyridine-Phthalimide Nano-Cocrystal: Release Rate and Oral Bioavailability Enhancement. European Journal of Pharmaceutical Sciences, 2017, 109, 581-586.

24. Jun-Hui Deng, Tong-Bu Lu, Changquan Calvin Sun, Jia-Mei Chen*. Dapagliflozin-Citric Acid Cocrystal Showing Better Solid State Properties than Dapagliflozin. European Journal of Pharmaceutical Sciences, 2017, 104, 255-261.

25. Xia-Lin Dai, Song Li, Jia-Mei Chen*, Tong-Bu Lu. Improving the Membrane Permeability of 5-Fluorouracil via Cocrystallization. Crystal Growth & Design, 2016, 16(8), 4430-4438.

26. Yong Chen, Long Li, Jia Yao, Yu-Yu Ma, Jia-Mei Chen*, Tong-Bu Lu*. Improving the Solubility and Bioavailability of Apixaban via Apixaban–Oxalic Acid Cocrystal. Crystal Growth & Design, 2016, 16(5), 2923-2930.

27. Rui-Zhen Lin, Peng-Jie Sun, Qian Tao, Jia Yao, Jia-Mei Chen*, Tong-Bu Lu. Mechanism Study on Stability Enhancement of Adefovir Dipivoxil by Cocrystallization: Degradation Kinetics and Structure-Stability Correlation. European Journal of Pharmaceutical Sciences, 2016, c85, 141-148.

28. 郭栋,宋嘉熙,李丹,陈嘉媚,林丽榕,鲁统部*,章慧*. 手性尼莫地平绝对构型的确定和关联物理化学学报. 2016, 32(9), 2241-2254.

29. Jia-Xi Song, Jia-Mei Chen*, Tong-Bu Lu*. Lenalidomide–Gallic Acid Cocrystals with Constant High Solubility. Crystal Growth & Design, 2015, 15(10), 4869-4875.

30. Ai-Yan Li, Lin-Lin Xu, Jia-Mei Chen*. Tong-Bu Lu*. Solubility and Dissolution Rate Enhancement of Triamterene by a Cocrystallization Method. Crystal Growth & Design, 2015, 15(8), 3785-3791.

31. Yan Yan, Jia-Mei Chen*, Tong-Bu Lu*. Thermodynamics and Preliminary Pharmaceutical Characterization of Melatonin-Pimelic Acid Cocrystal Prepared by a Melt Crystallization Method, CrystEngComm. 2015, 17(3), 612-620.

32. Jia-Mei Chen, Song Li, Tong-Bu Lu*. Pharmaceutical Cocrystals of Ribavirin with Reduced Release Rates, Crystal Growth & Design, 2014, 14(12), 6399-6408.

33. Jia Yao, Jia-Mei Chen*, Yi-Bo Xu, Tong-Bu Lu*. Enhancing the Solubility of 6-Mercaptopurine by Formation of Ionic Cocrystal with Zinc Trifluoromethanesulfonate: Single-Crystal-to- Single-Crystal Transformation. Crystal Growth & Design, 2014, 14(10), 5019-5025.

34. Song Li, Jia-Mei Chen*, Tong-Bu Lu*. Synthon Polymorphs of 1: 1 Co-crystal of 5-Fluorouracil and 4-Hydroxybenzoic Acid: Their Relative Stability and Solvent Polarity Dependence of Grinding Outcomes. CrystEngComm, 2014, 16(28), 6450-6458.

35. Jia-Xi Song, Yan Yan, Jia Yao, Jia-Mei Chen*, Tong-Bu Lu*. Improving the Solubility of Lenalidomide via Cocrystals. Crystal Growth & Design, 2014, 14(6), 3069-3077.

36. Jia Yao, Yong-Hui Mo, Jia-Mei Chen*, Tong-Bu Lu*. New Approach to Reduce the Overhigh Plasma Concentration of Captopril by the Formation of Zinc Coordination Polymer. Crystal Growth & Design, 2014, 14(5), 2599-2604.

37. Wen-Juan Ma, Jia-Mei Chen, Long Jiang, Jia Yao, Tong-Bu Lu*. The Delivery of Triamterene by Cucurbit[7]uril: Structures and Pharmacokinetics Study. Molecular Pharmaceutics, 2013, 10(12), 4698-4705.

38. Qian Tao, Jia-Mei Chen*, Tong-Bu Lu. Two Polymorphs and One Hydrate of a Molecular Salt Involving Phenazopyridine and Salicylic Acid. CrystEngComm, 2013, 15(39), 7852-7855.

39. Yan Yan, Jia-Mei Chen*, Tong-Bu Lu*. Simultaneously Enhancing the Solubility and Permeability of Acyclovir by Crystal Engineering Approach. CrystEngComm, 2013, 15(33), 6457-6460.

40. Na Geng, Jia-Mei Chen*, Zi-Jian Li, Long Jiang, Tong-Bu Lu*. Approach of Cocrystallization to Improve the Solubility and Photostability of Tranilast. Crystal Growth & Design, 2013, 13(8), 3546-3553.

41. Jia-Mei Chen, Tong-Bu Lu*. New Crystalline Forms of Mebendazole with n-Alkyl Carboxylic Acids: Neutral and Ionic Status. Chinese Journal of Chemistry, 2013, 31(5), 635-640.

42. Lin-Lin Xu, Jia-Mei Chen, Yan Yan, Tong-Bu Lu*. Improving the Solubility of 6?Mercaptopurine via Cocrystals and Salts. Crystal Growth & Design, 2012, 12(12), 6004-6011.

43. Zi-Zhou Wang, Jia-Mei Chen*, Tong-Bu Lu*. Enhancing the Hygroscopic Stability of s-Oxiracetam via Pharmaceutical Cocrystals. Crystal Growth & Design, 2012, 12(9), 4562-4566.

44. Jia-Mei Chen, Zi-Zhou Wang, Chuan-Bin Wu, Song Li, Tong-Bu Lu *. Crystal Engineering Approach to Improve the Solubility of Mebendazole. CrystEngComm, 2012, 14(19), 6221-6229.

45. Qian Tao, Jia-Mei Chen*, Lei Ma, Tong-Bu Lu*. Phenazopyridine Cocrystal and Salts that Exhibit Enhanced Solubility and Stability, Crystal Growth & Design, 2012, 12(6), 3144-3152.

46. Bing-Xin Zhao, Ying Wang*, Dong-Mei Zhang, Xiao-Jun Huang, Liang-Liang Bai, Yan Yan, Jia-Mei Chen, Tong-Bu Lu, Yi-Tao Wang, Qing-Wen Zhang*, Wen-Cai Ye*. Virosaines A and B, Two New Birdcage-Shaped Securinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa, Organic Letters, 2012, 14(12), 3096-3099.

47. Yan Yan, Jia-Mei Chen*, Na Geng, Tong-Bu Lu*. Improving the Solubility of Agomelatine via Cocrystals, Crystal Growth & Design, 2012, 12(5), 2226-2233.

48. Jia-Mei Chen, Chuan-Bin Wu, Tong-Bu Lu*. Application of Supramolecular Chemistry on Pharmaceutical Cocrystals, Chemical Journal of Chinese Universities, 2011, 32(9), 1996-2009.

49. Sai-Li Zheng, Jia-Mei Chen*, Wei-Xiong Zhang, Tong-Bu Lu*, Structures of Polymorphic Agomelatine and its Cocrystals with Acetic Acid and Ethylene Glycol, Crystal Growth & Design, 2011, 11(2), 466-471.