化工学报 ›› 2021, Vol. 72 ›› Issue (9): 4796-4807.doi: 10.11949/0438-1157.20201770

• 分离工程 • 上一篇    下一篇

添加剂作用下阿司匹林结晶模拟和实验研究

李闯1(),张扬1(),刘小娟1,王学重2()   

  1. 1.华南理工大学化学与化工学院,广东 广州 510640
    2.北京石油化工学院新材料与化工学院,北京市恩泽生物质 精细化工重点实验室,制药和结晶系统工程团队,北京 102617
  • 收稿日期:2020-12-09 修回日期:2021-08-02 出版日期:2021-09-05 发布日期:2021-09-05
  • 通讯作者: 张扬,王学重 E-mail:1508536927@qq.com;ceyzhang@scut.edu.cn;wangxuezhong@bipt.edu.cn
  • 作者简介:李闯(1994—),男,硕士研究生,1508536927@qq.com
  • 基金资助:
    国家自然科学基金重点项目(61633006);广东省应用型科技研发资金项目(2015B020232007);广东省自然科学基金项目(2017A030310262);广东省自然科学基金面上项目(2018A030313263);中央高校基本科研业务费专项资金(2017MS092);青海省科技计划项目(2021-GX-C10);北京石油化工学院恩泽生物质精细化工北京市重点实验室开放课题(药物连续结晶过程的在线监测和模拟)

Modeling and experimental study of additives on solution crystallization of aspirin

Chuang LI1(),Yang ZHANG1(),Xiaojuan LIU1,Xuezhong WANG2()   

  1. 1.School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, Guangdong, China
    2.Pharmaceutical and Crystallization Process System Engineering Group, Beijing City Key Laboratory of Enze Biomass Fine Chemicals, College of New Materials and Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, China
  • Received:2020-12-09 Revised:2021-08-02 Published:2021-09-05 Online:2021-09-05
  • Contact: Yang ZHANG,Xuezhong WANG E-mail:1508536927@qq.com;ceyzhang@scut.edu.cn;wangxuezhong@bipt.edu.cn

摘要:

晶体形貌作为晶体产品的重要质量指标,不仅会影响产品流动性、稳定性、溶出速率和生物可利用度等产品的质量指标,还会对过滤、干燥、压片等下游操作造成影响。通过分子模拟的方法指导阿司匹林冷却-反溶剂结晶过程的添加剂筛选,以添加剂作为晶体形貌的改性剂,降低阿司匹林晶体的长径比优化晶体形貌。通过单因素实验考查了添加剂浓度、晶种加入量、降温速率、搅拌速率和加水速率对阿司匹林晶体产品形貌、流动性和粒度分布等的影响,确定了较优的工艺条件。实验结果表明加入聚乙烯吡咯烷酮(PVP)作为添加剂可以降低阿司匹林晶体长径比,获得形貌为短棱柱状的晶体产品,能够显著改变晶体形貌优化产品的流动性。

关键词: 结晶, 阿司匹林, 分子模拟, 添加剂, 聚乙烯吡咯烷酮, 晶体形貌, 优化

Abstract:

As an important quality indicator of crystalline products, crystal morphology could have major impact not only on such quality measures as solid flowability, stability, dissolution rate and bioavailability, but also on downstream operations such as filtration, drying, and tableting. In this work, molecular simulation was used to guide the selection of additives in the cooling anti-solvent crystallization process of aspirin. The additives were used as crystal morphology modifiers to reduce the aspect ratio of aspirin crystals in order to optimize the crystal morphology. The effects of additive concentration, seed crystal addition, cooling rate, stirring rate and water addition rate on the morphology, flowability and particle size distribution of aspirin crystal products were examined to determine the appropriate experimental conditions. The experimental result showed that the addition of polyvinylpyrrolidone (PVP) as an additive can reduce the aspect ratio of aspirin crystals and obtain short prismatic crystal products, which can significantly change the crystal morphology and optimize the flowability of the product.

Key words: crystallization, aspirin, molecular simulation, additives, polyvinylpyrrolidone, crystal morphology, optimization

中图分类号: 

  • TQ

图 1

阿司匹林结晶实验装置示意图1—蠕动泵; 2—浊度仪; 3—二维成像系统; 4—浊度探头; 5—二维成像系统探头; 6—机械搅拌; 7—热电偶温度计探头; 8—250 ml四口结晶器; 9—温度控制器(Julabo FP51); 10—带有浊度和图像采集和处理软件的计算机"

图 2

阿司匹林晶胞、AE理论晶习及实验晶习"

表1

AE模型模拟得到的阿司匹林晶体理论晶习及晶面占总晶面面积百分比"

FaceMultiplicity面积占比/%
(1 0 0)251.93
(1 1 0)410.42
(0 1 1)411.44
(0 0 2)225.39
(1 1 -1)40.60
(1 1 1)40.22

图3

阿司匹林不同晶面上的原子及官能团分布"

图4

抑制阿司匹林晶体(0 1 1)面生长晶体形貌变化示意"

表2

添加剂在阿司匹林不同晶面的吸附能"

添加剂(聚合度)Eads/(kcal/mol)
(1 0 0)(1 1 0)(0 1 1)(0 0 2)(1 1 -1)(1 1 1)
PVP(45)-122.35-135.69-159.11-129.30-120.90-90.74
PVP(90)-220.06-237.32-277.11-207.90-180.92-148.76
PVP(135)-260.23-303.76-338.57-256.32-222.13-195.33
HPMC(100)-301.15-211.30-197.18-311.26-268.76-268.81

图 5

阿司匹林在不同含水量乙醇水溶剂中的质量溶解度拟合曲线"

表 3

阿司匹林质量溶解度拟合参数及最大溶解度"

T/Kb1b2b3b4b5最大溶解度Cmax×10-2/(g/g)w×10-2RMSD×10-2
278.15-2.1051.990-13.5718.80-16.6213.218.7720.1761
283.15-1.9211.953-11.0113.53-13.9816.1410.660.0716
293.15-1.5381.895-7.6091.179-0.70824.2012.800.1114
298.15-1.3492.144-9.4517.815-7.17029.6513.150.1393
303.15-1.1301.716-6.8012.970-3.92836.1713.530.1843
313.15-0.7901.934-6.4963.221-4.17852.9116.310.2273
323.15-0.4362.340-9.74517.81-17.6978.3720.210.3460
333.15-0.0820.5514.396-13.096.882121.034.970.6620

图6

不同添加剂实验条件下阿司匹林晶体产品形貌"

表4

不同添加剂条件下阿司匹林实验晶体长径比"

添加剂统计数目平均长径比
0601.93±0.32
0.05% PVP K13-18601.58±0.26
0.01% PVP K29-32721.63±0.22
0.05% PVP K29-32731.39±0.24
0.1% PVP K29-32641.10±0.21
0.05% PVP K88-96801.22±0.22
0.01% HPMC523.81±1.25
0.05% HPMC666.19±2.01
0.1% HPMC787.62±2.41

表5

单因素实验条件汇总"

实验 编号添加剂 浓度/%晶种量/%降温速率/ (K/min)搅拌速率/(r/min)加水速率/(ml/min)
1010.32505
20.0110.32505
30.0510.32505
40.1010.32505
50.0500.32505
60.050.50.32505
70.0530.32505
80.0510.12505
90.0510.52505
100.0510.31505
110.0510.33505
120.0510.325020
130.0510.3250一次性倾倒

表6

实验结果汇总"

实验编号D10/μmD50/μmD90/μm松装密度/(g/cm3)振实密度/(g/cm3)休止角/(°)收率/%CV/%
120154410300.410.524388.9156.37
21444388860.580.673388.6162.74
31443637120.720.782688.3357.13
41072704960.710.752988.1553.37
571.22695210.390.514588.7361.04
61052915490.530.633088.6558.01
713955810400.650.732887.8556.83
827957910800.610.733188.7551.13
914743711700.530.683587.3586.71
1035.347211100.430.564188.5583.96
111213589010.680.733088.4380.66
1286.62945700.730.772688.4158.21
1350.85429880.700.753088.1764.13
原料74.54599160.430.554067.81

图7

不同添加剂浓度下阿司匹林晶体形貌"

图8

不同晶种量条件下阿司匹林晶体形貌"

图9

未加晶种条件下的阿司匹林结晶过程成核生长的形貌变化二维监测图"

图10

不同降温速率条件下阿司匹林晶体形貌"

图11

不同搅拌速率条件下阿司匹林晶体形貌"

图12

不同加水速率条件下阿司匹林晶体形貌"

图13

阿司匹林原料与优化产品的显微镜形貌对比"

图 14

阿司匹林原料和优化产品PXRD表征结果"

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