药物共晶多晶型的研究进展

摘要

药物多晶型现象是影响药物稳定性和疗效的重要因素。近年来，越来越多的共晶体系被发现存在多晶型现象，而且不同晶型的共晶也表现出了性能上的差异。共晶多晶型的研究也因此受到了越来越多的关注。综述了近几年有关药物共晶多晶型的报道，解释了共晶多晶型的概念，并对其进行了分类（合成子多晶型、堆积多晶型、构象多晶型以及互变异构多晶型），重点介绍了目前共晶多晶型的筛选方法。此外，强调了共晶药物由于晶型不同而引起的性能差异。

	Service

	把本文推荐给朋友
	加入我的书架
	加入引用管理器
	Email Alert
	RSS
	作者相关文章
	王灵宇
	杜世超
	董伟兵

关键词：多晶型；药物共晶；晶型筛选

Abstract：

Pharmaceutical polymorphism is a critical factor that affects the stability and efficacy of the drug. In recent years, a growing number of pharmaceutical cocrystals have been found to be polymorphic and different polymorphs do show different properties. Accordingly, the research of polymorphism in cocrystals is attracting greater attention. In this contribution, the studies which focus on polymorphic cocrystals are reviewed. The concept of polymorphic cocrystals is explained and its different types are identified, including synthon polymorph, packing polymorph, conformational polymorph as well as tautomeric polymorph. The screening methods of polymorphic cocrystals are introduced in detail. Furthermore, the difference in the properties of pharmaceutical cocrystals due to different crystal forms is emphasized.

Keywords： polymorphism； pharmaceutical cocrystal； polymorph screening

Received 2018-04-01;

Fund:

国家自然科学基金创新研究群体项目（21621004）和国家科技重大专项（2017ZX09101001）。

Corresponding Authors: 董伟兵,E-mail:wbdong@tju.edu.cn。 Email: wbdong@tju.edu.cn

About author: 王灵宇(1994-),男,硕士研究生,现从事工业结晶方面的研究。

引用本文:

王灵宇, 杜世超, 董伟兵.药物共晶多晶型的研究进展[J]. 化学工业与工程, 2018,35(3): 29-37

Wang Lingyu, Du Shichao, Dong Weibing.Research advances of polymorphism in pharmaceutical cocrystals[J]. Chemcial Industry and Engineering, 2018,35(3): 29-37

[1] Bolla G, Nangia A. Pharmaceutical cocrystals:Walking the talk[J]. Chemical Communications,2016, 52(54):8342-8360
[2] Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties[J]. Crystal Growth & Design,2009, 9(6):2950-2967
[3] Cruz-Cabeza A J, Reutzel-Edens S M, Bernstein J. Facts and fictions about polymorphism[J]. Chemical Society Reviews, 2015, 44(23):8619-8635
[4] Almarsson O, Zaworotko M J. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?[J]. Chemical Communications, 2004,(17):1889-1896
[5] Vishweshwar P, Mcmahon J A, Peterson M L, et al. Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients[J]. Chemical Communications,2005,(36):4601-4603
[6] Vishweshwar P, Mcmahon J A, Bis J A, et al. Pharmaceutical co-crystals[J]. Journal of Pharmaceutical Sciences,2006, 95(3):499-516
[7] Aitipamula S, Chow P S, Tan R B H. Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients:Potential relevance to combination drugs[J]. Cryst Eng Comm, 2009, 11(11):1823-1827
[8] Ueto T, Takata N, Muroyama N, et al. Polymorphs and a hydrate of furosemide-nicotinamide 1:1 cocrystal[J]. Crystal Growth & Design,2012, 12(1):485-494
[9] Nanubolu J B, Ravikumar K. Designing a new cocrystal of olanzapine drug and observation of concomitant polymorphism in a ternary cocrystal system[J]. Cryst Eng Comm,2017, 19(2):355-366
[10] Bolla G, Nangia A. Binary and ternary cocrystals of sulfa drug acetazolamide with pyridine carboxamides and cyclic amides[J]. IUCrJ,2016, 3(2):152-160
[11] Aitipamula S, Chow P S, Tan R B H. Polymorphs and solvates of a cocrystal involving an analgesic drug, ethenzamide, and 3,5-dinitrobenzoic acid[J]. Crystal Growth & Design,2010, 10(5):2229-2238
[12] Lemmerer A, Adsmond D A, Esterhuysen C, et al. Polymorphic co-crystals from polymorphic co-crystal formers:Competition between carboxylic acid…pyridine and phenol…pyridine hydrogen bonds[J]. Crystal Growth & Design,2013, 13(9):3935-3952
[13] Sun C C. Cocrystallization for successful drug delivery[J]. Expert Opinion on Drug Delivery,2013, 10(2):201-213
[14] Aitipamula S, Chow P S, Tan R B H. Polymorphism in cocrystals:A review and assessment of its significance[J]. Cryst Eng Comm,2014, 16(17):3451-3465
[15] 张婷婷. 药物共晶的设计、合成与性质研究[D]. 长春:吉林大学, 2014 Zhang Tingting. Pharmaceutical co-crystal:Design, synthesis and characterization[D]. Changchun:Jilin University, 2014(in Chinese)
[16] Douroumis D, Ross S A, Nokhodchi A. Advanced methodologies for cocrystal synthesis[J]. Advanced Drug Delivery Reviews, 2017, 117:178-195
[17] Pindelska E, Sokal A, Kolodziejski W. Pharmaceutical cocrystals, salts and polymorphs:Advanced characterization techniques[J]. Advanced Drug Delivery Reviews, 2017, 117:111-146
[18] Bernstein J. Polymorphism in molecular crystals[M]. Oxford:Oxford University Press, 2002
[19] Hilfiker R. Polymorphism in the pharmaceutical industry[M]. Weinheim, Germany:Wiley-VCH, 2006
[20] Mukherjee A, Desiraju G R. Synthon polymorphism and pseudopolymorphism in co-crystals. The 4,4[prime or minute]-bipyridine-4-hydroxybenzoic acid structural landscape[J]. Chemical Communications, 2011, 47(14):4090-4092
[21] Schultheiss N, Roe M, Boerrigter S X M. Cocrystals of nutraceutical p-coumaric acid with caffeine and theophylline:Polymorphism and solid-state stability explored in detail using their crystal graphs[J]. Cryst Eng Comm, 2011, 13(2):611-619
[22] Li S, Chen J, Lu T. Synthon polymorphs of 1:1 co-crystal of 5-fluorouracil and 4-hydroxybenzoic acid:Their relative stability and solvent polarity dependence of grinding outcomes[J]. Cryst Eng Comm, 2014, 16(28):6450-6458
[23] Sarcevica I, Orola L, Veidis M V, et al. Cinnamic acid hydrogen bonds to isoniazid and N'-(propan-2-ylidene) isonicotinohydrazide, an in situ reaction product of isoniazid and acetone[J]. Acta Crystallographica, 2014, 70(4):392-395
[24] Susano M A, Martín-Ramos P, Maria T M R, et al. Co-Crystal of suberic acid and 1,2-bis(4-pyridyl)ethane:A new case of packing polymorphism[J]. Journal of Molecular Structure, 2017, 1147:76-83
[25] Braga D, Palladino G, Polito M, et al. Three polymorphic forms of the co-crystal 4,4'-bipyridine/pimelic acid and their structural, thermal, and spectroscopic characterization[J]. Chemistry-A European Journal, 2008, 14(32):10149-10159
[26] Aitipamula S, Chow P S, Tan R B H. Conformational and enantiotropic polymorphism of a 1:1 cocrystal involving ethenzamide and ethylmalonic acid[J]. Cryst Eng Comm, 2010, 12(11):3691-3697
[27] Childs S L, Hardcastle K I. Cocrystals of piroxicam with carboxylic acids[J]. Crystal Growth & Design, 2007, 7(7):1291-1304
[28] Qiao N, Li M, Schlindwein W, et al. Pharmaceutical cocrystals:An overview[J]. International Journal of Pharmaceutics, 2011, 419(1/2):1-11
[29] Leyssens T, Tumanova N, Robeyns K, et al. Solution cocrystallization, an effective tool to explore the variety of cocrystal systems:CAFFEINE/dicarboxylic acid cocrystals[J]. Cryst Eng Comm, 2014, 16(41):9603-9611
[30] Bevill M J, Vlahova P I, Smit J P. Polymorphic cocrystals of nutraceutical compound p-coumaric acid with nicotinamide:Characterization, relative solid-state stability, and conversion to alternate stoichiometries[J]. Crystal Growth & Design, 2014, 14(14):1438-1448
[31] Lee M J, Wang I C, Kim M J, et al. Controlling the polymorphism of carbamazepine-saccharin cocrystals formed during antisolvent cocrystallization using kinetic parameters[J]. Korean Journal of Chemical Engineering, 2015, 32(9):1-8
[32] Newman A. Specialized solid form screening techniques[J]. Organic Process Research & Development, 2013, 17(3):457-471
[33] Trask A V, Motherwell W D S, Jones W. Solvent-Drop grinding:Green polymorph control of cocrystallisation[J]. Chemical Communications, 2004, (7):890-891
[34] Fischer F, Heidrich A, Greiser S, et al. Polymorphism of mechanochemically synthesized cocrystals:A case study[J]. Crystal Growth & Design, 2016, 16(3):1701-1707
[35] Hasa D, Miniussi E, Jones W. Mechanochemical synthesis of multicomponent crystals:One liquid for one polymorph? A myth to dispel[J]. Crystal Growth & Design, 2016, 16(8):4582-4588
[36] Bhattacharya S, Saha B K. Guest-Induced isomerization of net and polymorphism in trimesic acid-arylamine complexes[J]. Crystal Growth & Design, 2011, 11(6):2194-2204
[37] Madusanka N, Eddleston M D, Arhangelskis M, et al. Polymorphs, hydrates and solvates of a co-crystal of caffeine with anthranilic acid[J]. Acta Crystallographica, 2014, 70(70):72-80
[38] Hasa D, Schneider R G, Voinovich D, et al. Cocrystal formation through mechanochemistry:From neat and liquid-assisted grinding to polymer-assisted grinding[J]. Angewandte Chemie International Edition, 2015, 54(25):7371-7375
[39] Hasa D, Carlino E, Jones W. Polymer-Assisted grinding, a versatile method for polymorph control of cocrystallization[J]. Crystal Growth & Design, 2016, 16(3):1772-1779
[40] Eddleston M D, Sivachelvam S, Jones W. Screening for polymorphs of cocrystals:A case study[J]. Cryst Eng Comm, 2013, 15(1):175-181
[41] Lang M, Grzesiak A L, Matzger A J. The use of polymer heteronuclei for crystalline polymorph selection[J]. Journal of the American Chemical Society, 2002, 124(50):14834-14835
[42] López-Mejías V, Knight J L, Brooks C L, et al. On the mechanism of crystalline polymorph selection by polymer heteronuclei[J]. Langmuir, 2011, 27(12):7575-7579
[43] Frank D S, Matzger A J. Influence of chemical functionality on the rate of polymer-induced heteronucleation[J]. Crystal Growth & Design, 2017, 17(8):4056-4059
[44] Porter I W W, Elie S C, Matzger A J. Polymorphism in carbamazepine cocrystals[J]. Crystal Growth & Design, 2008, 8(1):14-16
[45] Alhalaweh A, Kaialy W, Buckton G, et al. Theophylline cocrystals prepared by spray drying:Physicochemical properties and aerosolization performance[J]. AAPS Pharm Sci Tech, 2013, 14(1):265-276
[46] Grossjohann C, Serrano D R, Paluch K J, et al. Polymorphism in sulfadimidine/4-aminosalicylic acid cocrystals:Solid-State characterization and physicochemical properties[J]. Journal of Pharmaceutical Sciences, 2015, 104(4):1385-1398
[47] Zakharov B A, Losev E A, Boldyreva E V. Polymorphism of "glycine-glutaric acid" co-crystals:The same phase at low temperatures and high pressures[J]. Cryst Eng Comm, 2013, 15(9):1693-1697
[48] Lee R, Firbank A J, Probert M R, et al. Expanding the pyridine-formic acid cocrystal landscape under extreme conditions[J]. Crystal Growth & Design, 2016, 16(7):4005-4011
[49] Neumann M A, Van J D S, Fabbiani F P, et al. Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening[J]. Nature Communications, 2015, 6:7793
[50] Goud N R, Nangia A. Synthon polymorphs of sulfacetamide-acetamide cocrystal based on N-H…OS and N-H…OC hydrogen bonding[J]. Cryst Eng Comm, 2013, 15(37):7456-7461
[51] He H, Jiang L, Zhang Q, et al. Polymorphism observed in dapsone-flavone cocrystals that present pronounced differences in solubility and stability[J]. Cryst Eng Comm, 2015, 17(34):6566-6574
[52] Trask A V, Motherwell W D S, Jones W. Pharmaceutical cocrystallization:Engineering a remedy for caffeine hydration[J]. Crystal Growth & Design, 2005, 5(3):1013-1021
[53] Sangtani E, Sahu S K, Thorat S H, et al. Furosemide cocrystals with pyridines:An interesting case of color cocrystal polymorphism[J]. Crystal Growth & Design, 2015, 15(12):5858-5872