药学学报, 2021, 56(3): 855-864
引用本文:
任俊杰, 衡伟利, 周生研, 高缘, 张建军. 小分子无定形药物的凝胶化研究[J]. 药学学报, 2021, 56(3): 855-864.
REN Jun-jie, HENG Wei-li, ZHOU Sheng-yan, GAO Yuan, ZHANG Jian-jun. Gelation of small molecule amorphous drugs[J]. Acta Pharmaceutica Sinica, 2021, 56(3): 855-864.

小分子无定形药物的凝胶化研究
任俊杰1, 衡伟利2, 周生研2, 高缘2, 张建军1
1. 中国药科大学药学院, 江苏 南京 211198;
2. 中国药科大学中药学院, 江苏 南京 211198
摘要:
与药物晶态相比,无定形态呈长程无序的分子排列,常表现出较高的表观溶解度和溶出度。然而,一些小分子无定形药物在溶出期间会出现聚集成团的凝胶化现象,并表现出显著低于晶体药物的异常溶出行为。本研究旨在考察无定形药物凝胶化与其异常溶出之间的联系,探索凝胶形成的内在机制。通过熔融冷却法制备了辛伐他汀(simvastatin,SIM)、卡维地洛(carvedilol,CAR)和厄贝沙坦(irbesartan,IRB)的无定形态,凝胶形成导致这3种无定形药物的溶出显著低于其晶态,经扫描电子显微镜(scanning electron microscope,SEM)表征,所形成的凝胶为致密的三维网络结构。无定形SIM、CAR与IRB的临界凝胶温度分别为8~15℃、25~30℃和45~50℃,无定形CAR与IRB的临界凝胶pH值分别为1和0.25。凝胶形成的机制与无定形药物向过冷液态(作为重要的驱动力)的转变及在酸性条件下质子化引起的自组装密切相关。此外,水对无定形药物的润湿性及药物自身特性的差异也会影响凝胶化。
关键词:    无定形      溶出      凝胶化      过冷液态      温度      pH值     
Gelation of small molecule amorphous drugs
REN Jun-jie1, HENG Wei-li2, ZHOU Sheng-yan2, GAO Yuan2, ZHANG Jian-jun1
1. School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China;
2. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
Abstract:
Compared with crystalline drugs, their amorphous forms present long-range disordered molecular arrangements, and often exhibit higher apparent solubility and dissolution. However, several small molecule amorphous drugs may exhibit gelation phenomenon during the dissolution process, and show abnormal dissolution behavior with significantly lower dissolution than crystalline drugs. The current study aims to discover the relationship between the gelation of amorphous drugs and their abnormal dissolution, and further explore the internal gelation mechanism. Amorphous simvastatin (SIM), carvedilol (CAR), and irbesartan (IRB) were prepared by melt cooling method and characterized via X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR). Gel formation causes the dissolution of these three amorphous drugs to be significantly lower than their crystalline state. The formed gels were characterized as three-dimensional dense network structures by scanning electron microscope (SEM). Furthermore, amorphous SIM, CAR and IRB showed the critical gel temperature at 8-15℃, 25-30℃ and 45-50℃, and amorphous CAR and IRB showed the critical gel pH at 1 and 0.25. The mechanism of gel formation was proposed to be closely related to the transformation of amorphous drugs into the supercooled liquid state (as the important driving force) and the protonation induced self-assembling under acidic conditions. In addition, the wettability and properties of amorphous drugs also affect the formation of gelation.
Key words:    amorphous    dissolution    gelation    supercooled liquid state    temperature    pH   
收稿日期: 2020-09-08
DOI: 10.16438/j.0513-4870.2020-1466
基金项目: 国家自然科学基金资助项目(81703712,81773675,81873012);中国药科大学“双一流”建设项目(CPU2018GY11,CPU2018GY27).
通讯作者: 张建军,Tel/Fax:86-25-83379418,E-mail:amicute@163.com
Email: amicute@163.com
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参考文献:
[1] Pinnamaneni S, Das NG, Das S. Formulation approaches for orally administered poorly soluble drugs[J]. Die Pharm, 2002, 57:291-300.
[2] Perrut M, Jung J, Leboeuf F. Enhancement of dissolution rate of poorly-soluble active ingredients by supercritical fluid processes. Part I:Micronization of neat particles[J]. Int J Pharm, 2005, 288:3-10.
[3] Yao J, Shi NQ, Wang XL. The development of co-amorphous drug systems[J]. Acta Pharm Sin (药学学报), 2013, 48:648-654.
[4] Hao TY, Wei YF, Qian S, et al. Advances in strategies of improving solubility and permeability of taxanes[J]. Acta Pharm Sin (药学学报), 2018, 53:54-61.
[5] Yu L. Amorphous pharmaceutical solids:preparation, characterization and stabilization[J]. Adv Drug Deliv Rev, 2001, 48:27-42.
[6] Murdande SB, Pikal MJ, Shanker RM, et al. Solubility advantage of amorphous pharmaceuticals:I. A thermodynamic analysis[J]. J Pharm Sci, 2010, 99:1254-1264.
[7] Kim J, Kim M, Park HJ, et al. Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process[J]. Int J Pharm, 2008, 359:211-219.
[8] Wei Y, Zhou S, Hao T, et al. Further enhanced dissolution and oral bioavailability of docetaxel by coamorphization with a natural P-gp inhibitor myricetin[J]. Eur J Pharm Sci, 2019, 129:21-30.
[9] Wei Y, Ling Y, Su M, et al. Characterization and stability of amorphous tadalafil and four crystalline polymorphs[J]. Chem Pharm Bull, 2018, 66:1114-1121.
[10] Chawla G, Bansal AK. A comparative assessment of solubility advantage from glassy and crystalline forms of a water-insoluble drug[J]. Eur J Pharm Sci, 2007, 32:45-57.
[11] Burley JC, Duer MJ, Stein RS, et al. Enforcing Ostwald's rule of stages:isolation of paracetamol forms Ⅲ and Ⅱ[J]. Eur J Pharm Sci, 2007, 31:271-276.
[12] Guzman H, Tawa M, Zhang Z, et al. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations[J]. J Pharm Sci, 2007, 96:2686-2702.
[13] Qian S, Wang S, Li Z, et al. Charge-assisted bond N(+)H mediates the gelation of amorphous lurasidone hydrochloride during dissolution[J]. Int J Pharm, 2017, 518:335-341.
[14] Hancock BC, Zografi G. The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids[J]. Pharm Res, 1994, 11:471-477.
[15] Andronis V, Zografi G. Molecular mobility of supercooled amorphous indomethacin, determined by dynamic mechanical analysis[J]. Pharm Res, 1997, 14:410-414.
[16] Hamaura T, Kusai A, Nishimura K. Gel formation of cefpodoxime proxetil[J]. Stp Pharm Sci, 1995, 5:324-331.
[17] Kakumanu VK, Arora VK, Bansal AK. Investigation of factors responsible for low oral bioavailability of cefpodoxime proxetil[J]. Int J Pharm, 2006, 317:155-160.
[18] Hirrien M, Chevillard C, Desbrieres J, et al. Thermogelation of methylcelluloses:new evidence for understanding the gelation mechanism[J]. Polymer, 1998, 39:6251-6259.
[19] Nagarkar S, Nicolai T, Chassenieux C, et al. Structure and gelation mechanism of silk hydrogels[J]. Phys Chem Chem Phys, 2010, 12:3834-3844.
[20] Cheng J, Guo HH, Zhang JJ, et al. Physical and chemical properties of co-amorphous simvastatin-gliclazide[J]. J China Pharma Univ (中国药科大学学报), 2015, 46:301-308.
[21] Hao J. Study on Co-amorphous Carvedilol (共无定形卡维地洛的研究)[D]. Nanjing:China Pharmaceutical University (中国药科大学), 2014.
[22] Wei XB, Wang MY, Lu TT. Determination of irbesartan by HPLC[J]. Chin J Biochem Pharm (中国生化药物杂志), 2015, 35:141-143.
[23] Beyer P, Reinholz E. Thermodynamically stable modification of 1-(4-carbazolyl-oxy-3-[2-(2-methoxy phenoxy)-ethylamino]-2-propanole, process for its preparation and pharmaceutical compositions containing it. EP, 0893440A1[P]. 1999.
[24] Bocskei Z, Simon K, Rao R, et al. Irbesartan crystal form B[J]. Acta Crystallogr, 1998, 54:808-810.
[25] Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems[J]. J Pharm Sci, 1997, 86:1-12.
[26] Pokharkar VB, Mandpe L, Padamwar MN, et al. Development, characterization and stabilization of amorphous form of a low Tg drug[J]. Powder Technol, 2006, 167:20-25.
[27] Ambike AA, Mahadik KR, Paradkar A. Spray-dried amorphous solid dispersions of simvastatin, a low Tg drug:in vitro and in vivo evaluations[J]. Pharm Res, 2005, 22:990-998.
[28] Zhang F, Aaltonen J, Tian F, et al. Influence of particle size and preparation methods on the physical and chemical stability of amorphous simvastatin[J]. Eur J Pharm Biopharm, 2009, 71:64-70.
[29] Lobmann K, Strachan CJ, Grohganz H, et al. Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions[J]. Eur J Pharm Biopharm, 2012, 81:159-169.
[30] Wen X, Tan F, Jing Z, et al. Preparation and study the 1:2 inclusion complex of carvedilol with beta-cyclodextrin[J]. J Pharm Biomed Anal, 2004, 34:517-523.
[31] Hancock BC, Zografi G. The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids[J]. Pharm Res, 1994, 11:471-477.
[32] Estroff LA, Hamilton AD. Water gelation by small organic molecules[J]. Chem Rev, 2004, 104:1201-1218.
[33] Law D, Krill SL, Schmitt EA, et al. Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions[J]. J Pharm Sci, 2001, 90:1015-1025.
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