Citation: Zhong Zhi, Yang Xiaotong, Fu Xiao-Bin, Yao Ye-Feng, Guo Bao-Hua, Huang Yanbin, Xu Jun. Crystalline inclusion complexes formed between the drug diflunisal and block copolymers[J]. Chinese Chemical Letters, ;2017, 28(6): 1268-1275. doi: 10.1016/j.cclet.2017.04.001 shu

Crystalline inclusion complexes formed between the drug diflunisal and block copolymers

Zhong Zhi ^a ,
Yang Xiaotong ^a ,
Fu Xiao-Bin ^b ,
Yao Ye-Feng ^b ,
Guo Bao-Hua ^a ,
Huang Yanbin ^a,, ,
Xu Jun ^a,,

a.
Key Laboratory of Advanced Materials(MOE), Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
b.
Shanghai Key Laboratory of Magnetic Resonance, Institute of Functional Materials, School of Physics and Materials Science, East China Normal University, Shanghai 200062, China

Corresponding author: Huang Yanbin, yanbin@tsinghua.edu.cn Xu Jun, jun-xu@tsinghua.edu.cn
Received Date: 7 March 2017
Revised Date: 1 April 2017
Accepted Date: 1 April 2017
Available Online: 6 June 2017

Figures(8)

The solid form of drugs plays a central role in optimizing the physicochemical properties of drugs, and new solid forms will provide more options to achieve the desirable pharmaceutical profiles of drugs. Recently, certain drugs have been found to form crystalline inclusion complexes (ICs) with multiple types of linear polymers, representing a new subcategory of pharmaceutical solids. In this study, we used diflunisal (DIF) as the model drug host and extended the guest of drug/polymer ICs from homopolymers to block copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL). The block length in the guest copolymers showed a significant influence on the formation, thermal stability and dissolution behavior of the DIF ICs. Though the PEG block could hardly be included alone, it could indeed be included in the DIF ICs when the PCL block was long enough. The increase of the PCL block length produced IC crystals with improved thermal stability. The dissolution profiles of DIF/block copolymer ICs exhibited gradually decreased aqueous solubility and dissolution rate with the increasing PCL block length. These results demonstrate the possibility of using drug/polymer ICs to modulate the desired pharmaceutical profiles of drugs in a predictable and controllable manner.
- Pharmaceutical solid forms,
- Inclusion complexes,
- Drugs,
- Block copolymers,
- Thermal stability,
- Aqueous solubility,
- Dissolution profiles
1. [1]
  Gardner C.R., Walsh C.T., Almarsson O.. Drugs as materials:valuing physical form in drug discovery[J]. Nat. Rev. Drug Discovery, 2004,3:926-934. doi: 10.1038/nrd1550
2. [2]
  Kawabata Y., Wada K., Nakatani M., Yamada S., Onoue S.. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system:basic approaches and practical applications[J]. Int. J. Pharm., 2011,420:1-10. doi: 10.1016/j.ijpharm.2011.08.032
3. [3]
  Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J.. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J]. Adv. Drug Delivery Rev., 2001,46:3-26. doi: 10.1016/S0169-409X(00)00129-0
4. [4]
  Lipinski C.A.. Drug-like properties and the causes of poor solubility and poor permeability[J]. J. Pharmacol. Toxicol. Methods, 2000,44:235-249. doi: 10.1016/S1056-8719(00)00107-6
5. [5]
  Williams H.D., Trevaskis N.L., Charman S.A.. Strategies to address low drug solubility in discovery and development[J]. Pharmacol. Rev., 2013,65:315-499. doi: 10.1124/pr.112.005660
6. [6]
  Pudipeddi M., Serajuddin A.T.M.. Trends in solubility of polymorphs[J]. J. Pharm. Sci., 2005,94:929-939. doi: 10.1002/jps.20302
7. [7]
  Viscomi G.C., Campana M., Barbanti M.. Crystal forms of rifaximin and their effect on pharmaceutical properties[J]. CrystEngComm, 2008,10:1074-1081. doi: 10.1039/b717887e
8. [8]
  Babu N.J., Nangia A.. Solubility advantage of amorphous drugs and pharmaceutical cocrystals[J]. Cryst. Growth Des., 2011,11:2662-2679. doi: 10.1021/cg200492w
9. [9]
  Schultheiss N., Newman A.. Pharmaceutical cocrystals and their physicochemical properties[J]. Cryst. Growth Des., 2009,9:2950-2967. doi: 10.1021/cg900129f
10. [10]
  Bolla G., Nangia A.. Pharmaceutical cocrystals:walking the talk[J]. Chem. Commun., 2016,52:8342-8360. doi: 10.1039/C6CC02943D
11. [11]
  Duggirala N.K., Perry M.L., Almarsson O., Zaworotko M.J.. Pharmaceutical cocrystals:along the path to improved medicines[J]. Chem. Commun., 2016,52:640-655. doi: 10.1039/C5CC08216A
12. [12]
  Serajuddin A.T.M.. Salt formation to improve drug solubility[J]. Adv. Drug Delivery Rev., 2007,59:603-616. doi: 10.1016/j.addr.2007.05.010
13. [13]
  Avdeef A.. Solubility of sparingly-soluble ionizable drugs[J]. Adv. Drug Delivery Rev., 2007,59:568-590. doi: 10.1016/j.addr.2007.05.008
14. [14]
  Huang Y., Dai W.G.. Fundamental aspects of solid dispersion technology for poorly soluble drugs[J]. Acta Pharmacol. Sin. B, 2014,4:18-25. doi: 10.1016/j.apsb.2013.11.001
15. [15]
  Janssens S., Van den Mooter G.. Review:physical chemistry of solid dispersions[J]. J. Pharm. Pharmacol., 2009,61:1571-1586. doi: 10.1211/jpp.61.12.0001
16. [16]
  Zhong Z., Guo C., Yang X.. Drug molecule diflunisal forms crystalline inclusion complexes with multiple types of linear polymers[J]. Cryst. Growth Des., 2016,16:1181-1186. doi: 10.1021/acs.cgd.6b00010
17. [17]
  Zhong Z., Guo C., Chen L., Xu J., Huang Y.. Co-crystal formation between poly (ethylene glycol) and a small molecular drug griseofulvin[J]. Chem. Commun., 2014,50:6375-6378. doi: 10.1039/C4CC00159A
18. [18]
  Sun C.C.. Novel Co-crystals between polyethylene glycols and 5-phenylpyrazolyl-1-benzene-sulfonamides[J]. PCT Pat. Appl., 20062006/024930 A1.
19. [19]
  Yang X., Zhong Z., Huang Y.. The effect of PEG molecular weights on the thermal stability and dissolution behaviors of griseofulvin-PEG crystalline inclusion complexes[J]. Int. J. Pharm., 2016,508:51-60. doi: 10.1016/j.ijpharm.2016.05.014
20. [20]
  Zhong Z., Yang X., Guo B., Xu J., Huang Y.. Dissolution behavior of the crystalline inclusion complex formed by the drug diflunisal and poly (ε-caprolactone)[J]. Cryst. Growth Des., 2017,17:355-362. doi: 10.1021/acs.cgd.6b01578
21. [21]
  Porbeni F.E., Shin I.D., Shuai X.. Morphology and dynamics of the poly (ε-caprolactone)-b-poly(_L-lactide)diblock copolymer and its inclusion compound with α-cyclodextrin:A solid-state ¹³C NMR study[J]. J. Polym. Sci. Part B:Polym. Phys., 2005,43:2086-2096. doi: 10.1002/(ISSN)1099-0488
22. [22]
  Lu J., Shin I.D., Nojima S., Tonelli A.E.. Formation and characterization of the inclusion compounds between poly(ε-caprolactone)-poly(ethylene oxide)-poly(ε-caprolactone)triblock copolymer and α-and γ-cyclodextrin[J]. Polymer, 2000,41:5871-5883. doi: 10.1016/S0032-3861(99)00773-9
23. [23]
  Li J., Ni X., Zhou Z., Leong K.W.. Preparation and characterization of polypseudorotaxanes based on block-selected inclusion complexation between poly (propylene oxide)-poly(ethylene oxide)-poly (propylene oxide) triblock copolymers and α-cyclodextrin[J]. J. Am. Chem. Soc., 2003,125:1788-1795. doi: 10.1021/ja026623p
24. [24]
  Li X., Li J., Leong K.W.. Role of intermolecular interaction between hydrophobic blocks in block-selected inclusion complexation of amphiphilic poly (ethylene oxide)-poly[J]. Polymer, 2004,45:6845-6851. doi: 10.1016/j.polymer.2004.07.038
25. [25]
  Bracco S., Comotti A., Ferretti L., Sozzani P.. Supramolecular aggregation of block copolymers in the solid state as assisted by the selective formation of inclusion crystals[J]. J. Am. Chem. Soc., 2011,133:8982-8994. doi: 10.1021/ja201551n
26. [26]
  Vasanthan N., Shin I.D., Huang L., Nojima S., Tonelli A.E.. Formation, characterization, and segmental mobilities of block copolymers in their urea inclusion compound crystals[J]. Macromolecules, 1997,30:3014-3025. doi: 10.1021/ma970213h
27. [27]
  Martínez-Oha'rriz M.C., Martín C., Goñi M.M.. Polymorphism of diflunisal:Isolation and solid-state characteristics of a new crystal form[J]. J. Pharm. Sci., 1994,83:174-177. doi: 10.1002/jps.2600830212
28. [28]
  Cross W.I., Blagden N., Davey R.J.. A whole output strategy for polymorph screening:combining crystal structure prediction, graph set analysis, and targeted crystallization experiments in the case of diflunisal[J]. Cryst. Growth Des., 2003,3:151-158. doi: 10.1021/cg025589n
29. [29]
  Hansen L.K., Perlovich G.L., Bauer-Brandl A.. Diflunisal-hexane (4/1)[J]. Acta Crystallogr, Sect. E:Struct. Rep. Online, 2001,57:o604-o606. doi: 10.1107/S1600536801008558
30. [30]
  Hansen L.K., Perlovich G.L., Bauer-Brandl A.. The 1:1 hydrate of diflunisal[J]. Acta Crystallogr, Sect. E:Struct. Rep. Online, 2001,57:o477-o479. doi: 10.1107/S1600536801006973
31. [31]
  Sozzani P., Comotti A., Bracco S., Simonutti R.. Cooperation of multiple CH…π interactions to stabilize polymers in aromatic nanochannels as indicated by 2D solid state NMR[J]. Chem. Commun., 2004,7:768-769.
32. [32]
  Bracco S., Comotti A., Valsesia P., Beretta M., Sozzani P.. Self-assembly of 1, 4-cis-polybutadiene and an aromatic host to fabricate nanostructured crystals by CH…π interactions[J]. CrystEngComm, 2010,12:2318-2321. doi: 10.1039/c002931a
33. [33]
  Yan X., Peng B., Hu B., Chen Q.. PEO-urea-LiTFSI ternary complex as solid polymer electrolytes[J]. Polymer, 2016,99:44-48. doi: 10.1016/j.polymer.2016.06.056
34. [34]
  Kobr L., Zhao K., Shen Y., Michl J.. Inclusion compound based approach to arrays of artificial dipolar molecular rotors. A surface inclusion[J]. J. Am. Chem. Soc., 2012,134:10122-10131. doi: 10.1021/ja302173y
35. [35]
  Vanderhart D.L.. Influence of molecular packing on solid-state ¹³C chemical shifts:the n-alkane[J]. J. Magn. Reson., 1981,44:117-125.
36. [36]
  Pe'rez E., Vanderhart D.L.. Solid-state ¹³C nuclear magnetic resonance investigation of poly(oxetanes):effect of chain conformation[J]. Polymer, 1987,28:733-738. doi: 10.1016/0032-3861(87)90221-7
37. [37]
  Tonelli A.E.. Are the steric effects on the ¹³C-NMR chemical shifts of hydrocarbon polymers really long range[J]. Macromolecules, 1979,12:255-256. doi: 10.1021/ma60068a017
38. [38]
  Bittiger H., Marchessault R.H., Niegisch W.D.. Crystal structure of poly-ε-caprolactone, Acta Crystallogr[J]. Sect. B:Struct. Crystallogr. Cryst. Chem., 1970,26:1923-1927. doi: 10.1107/S0567740870005198
39. [39]
  Tadokoro H., Chatani Y., Yoshihara T., Tahara S., Murahashi S.. Structural studies on polyethers, [-(CH₂)_m-O-]_n. Ⅱ. Molecular structure of polyethylene oxide[J]. Makromol. Chem., 1964,73:109-127.
40. [40]
  Takahash Y., Sumita I., Tadokoro H.. Structural studies of polyethers. Ⅸ. Planar zigzag modification of poly(ethylene oxide)[J]. J. Polym. Sci., Part B:Polym. Phys., 1973,11:2113-2122. doi: 10.1002/pol.1973.180111103
41. [41]
  Tao J., Sun Y., Zhang G.G.Z., Yu L.. Solubility of small-molecule crystals in polymers:D-mannitol in PVP, indomethacin in PVP/VA, and nifedipine in PVP/VA[J]. Pharm. Res., 2009,26:855-864. doi: 10.1007/s11095-008-9784-z
42. [42]
  Lin D., Huang Y.. A thermal analysis method to predict the complete phase diagram of drug-polymer solid dispersions[J]. Int. J. Pharm., 2010,399:109-115. doi: 10.1016/j.ijpharm.2010.08.013
1. [1]
  Shehla Khalid , Muhammad Bilal , Nasir Rasool , Muhammad Imran . Photochemical reactions as synthetic tool for pharmaceutical industries. Chinese Chemical Letters, 2024, 35(9): 109498-. doi: 10.1016/j.cclet.2024.109498
2. [2]
  Guizhi Zhu , Junrui Tan , Longfei Tan , Qiong Wu , Xiangling Ren , Changhui Fu , Zhihui Chen , Xianwei Meng . Growth of CeCo-MOF in dendritic mesoporous organosilica as highly efficient antioxidant for enhanced thermal stability of silicone rubber. Chinese Chemical Letters, 2025, 36(1): 109669-. doi: 10.1016/j.cclet.2024.109669
3. [3]
  Shunshun Jiang , Ji Zhang , Jing Wang , Shan-Tao Zhang . Excellent energy storage properties in non-stoichiometric Bi_0.5Na_0.5TiO₃-based relaxor ferroelectric ceramics. Chinese Chemical Letters, 2024, 35(7): 108955-. doi: 10.1016/j.cclet.2023.108955
4. [4]
  Bo Yang , Pu-An Lin , Tingwei Zhou , Xiaojia Zheng , Bing Cai , Wen-Hua Zhang . Facile surface regulation for highly efficient and thermally stable perovskite solar cells via chlormequat chloride. Chinese Chemical Letters, 2024, 35(10): 109425-. doi: 10.1016/j.cclet.2023.109425
5. [5]
  Kezhen Qi , Shu-yuan Liu , Ruchun Li . Selective dissolution for stabilizing solid electrolyte interphase. Chinese Chemical Letters, 2024, 35(5): 109460-. doi: 10.1016/j.cclet.2023.109460
6. [6]
  Qian Wang , Yeping Bian , Gagan Dhawan , Wei Zhang , Alexander E. Sorochinsky , Ata Makarem , Vadim A. Soloshonok , Jianlin Han . FDA approved fluorine-containing drugs in 2023. Chinese Chemical Letters, 2024, 35(11): 109780-. doi: 10.1016/j.cclet.2024.109780
7. [7]
  Hong Chen , Mao-Yin Ran , Long-Hua Li , Xin-Tao Wu , Hua Lin . [Cs14Cl][Tm71Se110]: An unusual salt-inclusion chalcogenide containing different valent Tm centers and ultralow thermal conductivity. Chinese Journal of Structural Chemistry, 2024, 43(10): 100397-100397. doi: 10.1016/j.cjsc.2024.100397
8. [8]
  Yingjie Wang , Peng Tang , Wenchao Tu , Qi Gao , Cuizhu Wang , Luying Tan , Lixin Zhao , Hongye Han , Liefeng Ma , Kouharu Otsuki , Weilie Xiao , Wenli Wang , Jinping Liu , Yong Li , Zhajun Zhan , Wei Li , Xianli Zhou , Ning Li . Highly anticipated natural diterpenoids as an important source of new drugs in 2013–2023. Chinese Chemical Letters, 2025, 36(1): 109955-. doi: 10.1016/j.cclet.2024.109955
9. [9]
  Lingjiang Kou , Yong Wang , Jiajia Song , Taotao Ai , Wenhu Li , Mohammad Yeganeh Ghotbi , Panya Wattanapaphawong , Koji Kajiyoshi . Mini review: Strategies for enhancing stability of high-voltage cathode materials in aqueous zinc-ion batteries. Chinese Chemical Letters, 2025, 36(1): 110368-. doi: 10.1016/j.cclet.2024.110368
10. [10]
  Xinzhi Ding , Chong Liu , Jing Niu , Nan Chen , Shutao Xu , Yingxu Wei , Zhongmin Liu . Solid-state NMR study of the stability of MOR framework aluminum. Chinese Journal of Structural Chemistry, 2024, 43(4): 100247-100247. doi: 10.1016/j.cjsc.2024.100247
11. [11]
  Yunjie Dang , Yanru Feng , Xiao Chen , Chaoxing He , Shujie Wei , Dingyang Liu , Jinlong Qi , Huaxing Zhang , Shaokun Yang , Zhiyun Niu , Bai Xiang . Development of a multi-level pH-responsive lipid nanoplatform for efficient co-delivery of siRNA and small-molecule drugs in tumor treatment. Chinese Chemical Letters, 2024, 35(12): 109660-. doi: 10.1016/j.cclet.2024.109660
12. [12]
  Zhe Li , Ping-Zhao Liang , Li Xu , Fei-Yu Yang , Tian-Bing Ren , Lin Yuan , Xia Yin , Xiao-Bing Zhang . Three positive charge nonapoptotic-induced photosensitizer with excellent water solubility for tumor therapy. Chinese Chemical Letters, 2024, 35(8): 109190-. doi: 10.1016/j.cclet.2023.109190
13. [13]
  Jingjing Zhang , Lan Ding , Vadim Popkov , Kezhen Qi . Aqueous indium metal batteries. Chinese Chemical Letters, 2025, 36(2): 110407-. doi: 10.1016/j.cclet.2024.110407
14. [14]
  Xue Zhao , Rui Zhao , Qian Liu , Henghui Chen , Jing Wang , Yongfeng Hu , Yan Li , Qiuming Peng , John S Tse . A p-d block synergistic effect enables robust electrocatalytic oxygen evolution. Chinese Chemical Letters, 2024, 35(11): 109496-. doi: 10.1016/j.cclet.2024.109496
15. [15]
  Yiwen Lin , Yijie Chen , Chunhui Deng , Nianrong Sun . Integration of resol/block-copolymer carbonization and machine learning: A convenient approach for precise monitoring of glycan-associated disorders. Chinese Chemical Letters, 2024, 35(12): 109813-. doi: 10.1016/j.cclet.2024.109813
16. [16]
  Juan Guo , Mingyuan Fang , Qingsong Liu , Xiao Ren , Yongqiang Qiao , Mingju Chao , Erjun Liang , Qilong Gao . Zero thermal expansion in Cs₂W₃O₁₀. Chinese Chemical Letters, 2024, 35(7): 108957-. doi: 10.1016/j.cclet.2023.108957
17. [17]
  Ruizhi Yang , Xia Li , Weiping Guo , Zixuan Chen , Hongwei Ming , Zhong-Zhen Luo , Zhigang Zou . New thermoelectric semiconductors Pb5Sb12+xBi6-xSe32 with ultralow thermal conductivity. Chinese Journal of Structural Chemistry, 2024, 43(3): 100268-100268. doi: 10.1016/j.cjsc.2024.100268
18. [18]
  Chaozheng He , Pei Shi , Donglin Pang , Zhanying Zhang , Long Lin , Yingchun Ding . First-principles study of the relationship between the formation of single atom catalysts and lattice thermal conductivity. Chinese Chemical Letters, 2024, 35(6): 109116-. doi: 10.1016/j.cclet.2023.109116
19. [19]
  Zhiqing Ge , Zuxiong Pan , Shuo Yan , Baoying Zhang , Xiangyu Shen , Mozhen Wang , Xuewu Ge . Novel high-temperature thermochromic polydiacetylene material and its application as thermal indicator. Chinese Chemical Letters, 2024, 35(11): 109850-. doi: 10.1016/j.cclet.2024.109850
20. [20]
  Jingyuan Yang , Xinyu Tian , Liuzhong Yuan , Yu Liu , Yue Wang , Chuandong Dou . Enhancing stability of diradical polycyclic hydrocarbons via P=O-attaching. Chinese Chemical Letters, 2024, 35(8): 109745-. doi: 10.1016/j.cclet.2024.109745

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(908)
HTML views(13)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142