Screening, characterization and property evaluation of dipyridamole eutectic drug system

doi:10.3969/j.issn.1000-1565.2023.04.007

Abstract

Abstract: Two component binary phase diagram analysis method was used to screen the eutectic system of the insoluble drug dipyridamole, and DSC, PXRD and FTIR techniques were used to characterize it. Subsequently, the solubility and dissolution of dipyridamole in the eutectic system were studied, and the solubilization mechanism of the eutectic system was studied by fluorescence quenching and phase solubility methods. The results showed that dipyridamole and nicotinamide formed a “V” type binary phase diagram with a single melting point, which proved that they formed a eutectic system. The solubility and dissolution rate of dipyridamole were improved by this system. Fluorescence spectra showed that there was a complexation effect between dipyridamole and nicotinamide. The phase solubility results further showed that a soluble complex was formed between the two, and the molar ratio of 1∶1. The complexation constants at 25 ℃ and 37 ℃ were 150.22 L/mol and 85.14 L/mol, respectively. The complexation reaction was endothermic, and the temperature rise was not conducive to the complexation of dipyridamole and nicotinamide.

Key words: dipyridamole, nicotinamide, eutectic, complex

CLC Number:

R944

LI Yuanchun,DONG Xueqing,LI Congwei,AN Qingqing,YANG Caiqin. Screening, characterization and property evaluation of dipyridamole eutectic drug system[J]. Journal of Hebei University(Natural Science Edition), 2023, 43(4): 387-394.

References

[1] KIMOTO K, YAMAMOTO M, KARASHIMA M, et al. Pharmaceutical cocrystal development of TAK-020 with enhanced oral absorption[J]. Crystals, 2020, 10(3): 211. DOI: 10.3390/cryst10030211.
[2] FAROQUE M U, NOUREEN S, AHMED M, et al. Electrostatic properties of the pyrimethamine-2, 4-dihydroxybenzoic acid cocrystal in methanol studied using transferred electron-density parameters[J]. Acta Crystallogr C Struct Chem, 2018, 74(1): 100-107. DOI: 10.1107/S2053229617017788.
[3] THAKURIA R, DELORI A, JONES W, et al. Pharmaceutical cocrystals and poorly soluble drugs[J]. Int J Pharm, 2013, 453(1): 101-125. DOI: 10.1016/j.ijpharm.2012.10.043.
[4] KIGUCHIYA A, TERAOKA R, SAKANE T, et al. A new method for classification of salts and cocrystals using solid-state UV spectrophotometry[J]. Chem Pharm Bull(Tokyo), 2019, 67(9): 945-952. DOI: 10.1248/cpb.c18-00743.
[5] LEUNER C, DRESSMAN J. Improving drug solubility for oral delivery using solid dispersions[J]. Eur J Pharm Biopharm, 2000, 50(1):47-60. DOI: 10.1016/s0939-6411(00)00076-x.
[6] BAZZO G C, PEZZINI B R, STULZER H K. Eutectic mixtures as an approach to enhance solubility, dissolution rate and oral bioavailability of poorly water-soluble drugs[J]. Int J Pharm, 2020, 588: 119741. DOI: 10.1016/j.ijpharm.2020.119741.
[7] CHADHA K, KARAN M, CHADHA R, et al. Is failure of cocrystallization actually a failure eutectic formation in cocrystal screening of hesperetin[J]. J PHARM SCI, 2017,106(8): 2026-2036.DOI: 10.1016/j.xphs.2017.04.038.
[8] KAPIL N, DATTA Y H, ALAKBAROVA N, et al. Antiplatelet and anticoagulant therapies for prevention of ischemic stroke[J]. Clin Appl Thromb Hemost, 2017, 23(4): 301-318. DOI: 10.1177/1076029616660762.
[9] 王德光.双嘧达莫联合阿司匹林肠溶片治疗脑血栓的临床疗效分析[J].中国现代药物应用, 2022, 16(19): 90-92. DOI: 10.14164/j.cnki.cn11-5581/r.2022.19.027.
[10] LONGO J, PANDYRA A A, STACHURA P, et al. Cyclic AMP-hydrolyzing phosphodiesterase inhibitors potentiate statin-induced cancer cell death[J]. Mol Oncol, 2020, 14(10): 2533-2545. DOI: 10.1002/1878-0261.12775.
[11] 田霞,丁江生,范云周,等.制剂新技术在双嘧达莫新剂型中的研究进展[J].国际药学研究杂志, 2018, 45(4): 253-257. DOI: 10.13220/j.cnki.jipr.2018.04.002.
[12] REDDY N H S, PATNALA S, KANFER I. Investigation of biowaivers for immediate release formulations containing BCS Ⅲ drugs, acyclovir, atenolol, and ciprofloxacin hydrochloride, using dissolution testing[J]. AAPS Pharm Sci Tech, 2017, 18(2): 424-431. DOI: 10.1208/s12249-016-0520-4.
[13] TANIGUCHI C, INOUE R, KATO M, et al. New dipyridamole salt with improved dissolution and oral bioavailability under hypochlorhydric conditions[J]. Drug Metab Pharmacokinet, 2013, 28(5): 383-390. DOI: 10.2133/dmpk.DMPK-12-RG-139.
[14] XI Z J, SHARMA N, PAPRIKAR A, et al. Development and evaluation of dipyridamole sustained release tablets containing micro-environmental pH modifiers[J]. J Drug Deliv Sci Technol, 2019, 54(9): 101231. DOI: 10.1016/j.jddst.2019.101231.
[15] MAGHSOODI M, NOKHODCHI A, BABI H I. Rational selection of formulation components to improve dissolution of Dipyridamole[J]. J Drug Deliv Sci Technol, 2020, 55: 101467. DOI: 10.1016/j.jddst.2019.101467.
[16] PARK H, SEO H J, HA E S, et al. Preparation and characterization of glimepiride eutectic mixturewith l-arginine for improvement of dissolution rate[J]. Int J Pharm, 2020, 581: 119288. DOI: 10.1016/j.ijpharm.2020.119288.
[17] 张跃勇,田佳鑫,吕琳,等.吡罗昔康-苯甲酸共晶的制备与体外释放研究[J].中国新药杂志, 2018, 27(1): 91-96. DOI: 10.3969/j.issn.1671-2560.2007.01.003.
[18] 翟立海,夏祥来,张洪美,等.奥希替尼-苹果酸-丙酮合物共晶的合成、晶体结构及性质研究[J].山东化工, 2022, 51(8):5-8. DOI: 10.3969/j.issn.1008-021X.2022.08.002.
[19] ZHOU H, WANG Y, LI S T, et al. Improving chemical stability of resveratrol in hot melt extrusionbased on formation of eutectic with nicotinamide[J]. Int J Pharm, 2021, 607: 121042. DOI: 10.1016/j.ijpharm.2021.121042.
[20] GUO W, LI C W, DU P F, et al. Thermal properties of drug polymorphs: A case study with felodipine form I and form Ⅳ[J]. J Saudi Chem Soc, 2020, 24(6): 474-483. DOI: 10.1016/j.jscs.2020.04.003.
[21] 国家药典委员会.中华人民共和国药典(二部)[S].北京:中国医药科技出版社, 2020:0931.
[22] BAGHEL S, CATHCART H, REDINGTON W, et al. An investigation into the crystallization tendency/kinetics of amorphous active pharmaceutical ingredients: A case study with dipyridamole and cinnarizine[J]. Eur J Pharm Biopharm, 2016, 104: 59-71. DOI: 10.1016/j.ejpb.2016.04.017.
[23] 庞丽丽,陈美玲,陆杰.来那度胺-烟酰胺共晶的制备与表征[J].应用化工, 2015, 44(2): 203-205. DOI: 10.3969/j.issn.1000-5269.2003.01.007.
[24] PATEL R D, RAVAL M K, PETHANI T M,et al. Influence of eutectic mixture as a multi-component system in the improvement of physicomechanical and pharmacokinetic properties of diacerein[J]. Adv Powder Technol, 2020, 31(4): 1441-1456. DOI: 10.1016/j.apt.2020.01.021.
[25] PATEL R D, RAVAL M K, BAGATHARIYA A A, et al. Functionality improvement of Nimesulide by eutectic formation with nicotinamide: exploration using temperature-composition phase diagram[J]. Adv Powder Technol, 2019, 30(5): 961-973. DOI: 10.1016/j.apt.2019.02.010.
[26] GUPTA P, AGRAWAL T, DAS S S, et al. Phase equilibria and molecular interaction studies on(naphthols+vanillin)systems[J]. J Chem Thermodyn, 2012, 48: 291-299. DOI: 10.1016/j.jct.2012.01.001.
[27] 蔡雅琴.“丹皮酚—薄荷脑”低共熔物纳米乳凝胶的制备与评价[D].银川:宁夏医科大学.
[28] DUAN M J, BAI J K, YANG J, et al. Molecular recognition and binding of CcrA from Bacteroides fragilis with cefotaxime and ceftazidime by fluorescence spectra and molecular docking[J]. J Biol Inorg Chem, 2022, 27(3): 283-295. DOI: 10.1007/s00775-022-01927-6.
[29] DITTERT L W, HIGUCHI T, REESE D R. Phase solubility technique in studying the formation of complex salts of triamterene[J]. J Pharm Sci, 1964, 53(11): 1325-1328. DOI: 10.1002/jps.2600531108. (