聚合物辅料对阿司匹林结晶动力学影响机制的非平衡热力学建模及预测

doi:10.11949/0438-1157.20201192

摘要/Abstract

摘要：

探究聚合物辅料对难溶性药物结晶的影响机制，是指导无定形固体分散体制剂设计和制备中辅料筛选的关键。研究了不同因素（温度、搅拌速率、聚合物浓度、聚合物分子量和聚合物种类等）对阿司匹林晶体生长动力学的影响。首先，采用基于三种不同晶体生长机制的化学势梯度模型结合UNIQUAC活度系数模型，描述和预测了阿司匹林在不同条件下的结晶动力学。进一步分析了不同因素对晶体生长速率常数 $k_{t}$ 和结晶热力学推动力 $? μ$ 的影响以及对阿司匹林结晶动力学的影响机制。结果表明，阿司匹林晶体生长速率随着结晶温度、聚合物浓度的增加而降低，随搅拌速率的增加而升高；聚乙烯吡咯烷酮（PVP K25）和羟丙基甲基纤维素（HPMC E3）显著抑制了阿司匹林的晶体生长，在PVP K25和HPMC E3水溶液体系下阿司匹林的晶体生长属于二维成核机制，在纯水和PEGs水溶液体系下晶体生长属于粗糙生长机制。所采用的化学势梯度模型能很好预测不同温度和搅拌速率下阿司匹林的结晶动力学，可有效减少实验所需的人力、物力和财力。研究可为固体分散体制剂制备中聚合物的筛选提供理论研究基础。

关键词: 固液相平衡, 活度系数, 结晶抑制, 聚合物辅料, 动力学模型, 非平衡热力学

Abstract:

Exploring the mechanism of the influence of polymer excipients on the crystallization of insoluble drugs is the key to guide the design of amorphous solid dispersion formulations and the selection of excipients in the preparation. The effects of different factors (temperature, stirring rate, polymer concentration, molecular weight and polymer type) on the growth kinetics of aspirin crystal were studied. Firstly, the chemical potential gradient model based on three different crystal growth mechanisms and the UNIQUAC activity coefficient model were used to describe and predict the crystallization kinetics of aspirin under different conditions. The effects of different factors on the growth constant $k_{t}$ and crystallization driving force $? μ$ of aspirin were studied. The results showed that the crystal growth rate of aspirin decreased with the increase of crystallization temperature and polymer concentration, but increased with the increase of stirring rate. Polyvinylpyrrolidone (PVP K25) and hydroxypropyl methyl cellulose (HPMC E3) significantly inhibited the crystal growth of aspirin. The crystal growth of aspirin in HPMC E3 aqueous solution belongs to two-dimensional nucleation mechanism, while the crystal growth in pure water and PEGs aqueous solution belongs to adhesion growth mechanism. The chemical potential gradient model used in this paper can well predict the crystallization kinetics of aspirin at different temperatures and stirring speeds, which can effectively reduce the manpower, material and financial resources required for the experiment. This study can provide theoretical basis for the selection of polymers in the preparation of solid dispersions.

Key words: solid liquid equilibrium, activity coefficient, crystal inhibition, polymer excipients, dynamic model, nonequilibrium thermodynamics

中图分类号:

TQ 460.6

吉远辉, 陈俏, 翁靖云. 聚合物辅料对阿司匹林结晶动力学影响机制的非平衡热力学建模及预测[J]. 化工学报, 2021, 72(1): 508-520.

JI Yuanhui, CHEN Qiao, WENG Jingyun. Nonequilibrium thermodynamic modeling and prediction of the effect of polymer excipients on aspirin crystallization kinetics[J]. CIESC Journal, 2021, 72(1): 508-520.

图/表 11

表1 不同物质的基团贡献参数[29]

Table 1 Group contribution parameters of different substances[29]

Substance	r_i	q_i	V_m/(cm³/mol)
aspirin	6.06	4.792	133.45
water	0.92	1.4	18.01
PEG 6000	153.57	122.86	5244.76
PEG 400	10.41	8.33	355.40
PVP K25	614.29	491.43	20979.02
HPMC E3	128.33	102.66	4382.73

图1 分子结构式

Fig.1 Structural formula of aspirin, polyethylene glycol, polyvinylpyrrolidone and hydroxypropyl methylcellulose

图2 温度和搅拌速率对阿司匹林晶体生长动力学的影响

Fig.2 Effect of temperature and stirring speed on the growth kinetics of aspirin

图3 聚合物浓度和种类对阿司匹林晶体生长动力学的影响

Fig.3 Effect of concentration and type of polymers on the growth kinetics of aspirin

表2 阿司匹林体系中UNIQUAC模型相互作用参数[29]

Table 2 Interaction parameters of UNIQUAC model for aspirin[29]

聚合物	u₁₂-u₂₂/ (J/mol)	u₂₁-u₁₁/(J/mol)	u₁₃-u₃₃/(J/mol)	u₃₁-u₁₁/(J/mol)	u₂₃-u₃₃/(J/mol)	u₃₂-u₂₂/(J/mol)
水	1550.6	-478.0	—	—	—	—
PEG6000	-863.6	1204.0	-1095.3	2093.6	6499.4	693.9
PEG400	-3519.8	527.7	-70.3	793.5	19384.3	-3247.7
PVP K25	-388.8	404.2	-344.9	966.5	8917.7	290.1
HPMC E3	5281.8	9436.2	11811.2	-1986.7	6731.0	-5450.8

图4 阿司匹林晶体生长理论模型计算结果对比

Fig.4 Comparison of calculated results of aspirin crystal growth kinetics with experimental results

表3 阿司匹林在不同条件下的平衡浓度、生长机理及计算值和实验值之间的平均相对偏差

Table 3 The equilibrium concentration and growth mechanism of aspirin under different crystallization conditions and the ARD between the calculated and experimental values

结晶条件	平衡浓度/(g/L)	生长机制	ARD/%
纯水溶液，283.15 K，200 r/min	2.11	粗糙生长机制	4.32
纯水溶液，288.15 K，200 r/min	2.74	粗糙生长机制	3.43
纯水溶液，288.15 K，100 r/min	2.74	粗糙生长机制	3.86
2% PEG 6000水溶液，288.15 K，200 r/min	3.22	粗糙生长机制	1.93
5% PEG 6000水溶液，288.15 K，200 r/min	3.59	粗糙生长机制	1.21
2% PEG 400水溶液，288.15 K，200 r/min	3.11	粗糙生长机制	1.50
2% HPMC E3水溶液，288.15 K，200 r/min	4.33	二维成核生长机制	0.76
2% PVP K25水溶液，288.15 K，200 r/min	4.13	二维成核生长机制	0.61

图5 阿司匹林在纯水体系不同温度和搅拌速率下的晶体生长动力学实验和模型预测结果

Fig.5 Aspirin crystal growth kinetics at different temperatures and stirring speeds in water

图6 不同条件下阿司匹林晶体生长速率常数kt?

Fig.6 kt of aspirin under different conditions

图7 纯水体系中不同因素对阿司匹林结晶热力学推动力?μ的影响

Fig.7 Effect of different factors on ?μ of aspirin in water

图8 PEG 6000的浓度(a)和不同种类的聚合物(b)对阿司匹林结晶热力学推动力?μ的影响

Fig.8 Effect of PEG 6000 concentration (a) and different kinds of polymers (b) on ?μ of aspirin

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