Nonequilibrium thermodynamic modeling and prediction of the effect of polymer excipients on aspirin crystallization kinetics

doi:10.11949/0438-1157.20201192

Abstract

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

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

CLC Number:

TQ 460.6

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.

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.

Figures/Tables 11

References 38

1	Baghel S, Cathcart H, O'Reilly N J. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class Ⅱ drugs[J]. Journal of Pharmaceutical Sciences, 2016, 105(9): 2527-2544.
2	Yasir M, Asif M, Kumar A, et al. Biopharmaceutical classification system: an account[J]. International Journal of Pharmtech Research, 2010, 2(3): 1681-1690.
3	Marsac P J, Li T L, Taylor L S. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters[J]. Pharmaceutical Research, 2009, 26(1): 139-151.
4	Newman A, Knipp G, Zografi G. Assessing the performance of amorphous solid dispersions[J]. Journal of Pharmaceutical Sciences, 2012, 101(4): 1355-1377.
5	Sun D D, Ju T C R, Lee P I. Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels[J]. European Journal of Pharmaceutics & Biopharmaceutics, 2012, 81(1): 149-158.
6	Tran P H L, Duan W, Lee B J, et al. Modulation of drug crystallization and molecular interactions by additives in solid dispersions for improving drug bioavailability[J]. Current Pharmaceutical Design, 2019, 25(18): 2099-2107.
7	吕江维, 孙晗, 魏亚青, 等. 介孔硅材料提高难溶性药物生物利用度的研究进展[J]. 药学研究, 2018, 37(6): 361-364.
	Lyu J W, Sun H, Wei Y Q, et al. Research progress of mesoporous silicon materials for improving bioavailability of insoluble drugs[J]. Journal of Pharmaceutical Research, 2018, 37(6): 361-364.
8	Zhu Q, Harris M T, Taylor L S. Modification of crystallization behavior in drug/polyethylene glycol solid dispersions[J]. Molecular Pharmaceutics, 2012, 9(3): 546-553.
9	Gruberova L, Kratochvil B. Solid dispersions of poorly water soluble drug[J]. Chemicke Listy, 2019, 113(6): 383-390.
10	Huang Y B, Dai W G. Fundamental aspects of solid dispersion technology for poorly soluble drugs[J]. Acta Pharmaceutica Sinica B, 2014, 4(1): 18-25.
11	赵绍磊, 王耀国, 张腾, 等. 制药结晶中的先进过程控制[J]. 化工学报, 2020, 71(2): 459-474.
	Zhao S L, Wang Y G, Zhang T, et al. Advanced process control of pharmaceutical crystallization[J]. CIESC Journal, 2020, 71(2): 459-474.
12	Zhou L, Wang Z, Zhang M J, al et, Determination of metastable zone and induction time of analgin for cooling crystallization[J]. Chinese Journal of Chemical Engineering, 2017, 25(3): 313-318.
13	张璐, 马丹阳, 唐星, 等. 高载药量尼莫地平无定形固体分散体溶出及稳定性研究[J]. 中国药剂学杂志, 2020, 18(1): 38-48.
	Zhang L, Ma D Y, Tang X, et al. Dissolution and stability of high-loaded nimodipine amorphous solid dispersion[J]. Chinese Journal of Pharmaceutics, 2020, 18(1): 38-48.
14	Liu H, Taylor L S, Edgar K J. The role of polymers in oral bioavailability enhancement: a review[J]. Polymer, 2015, 77: 399-415.
15	Ji Y H, Paus R, Prudic A, et al. A novel approach for analyzing the dissolution mechanism of solid dispersions[J]. Pharmaceutical Research, 2015, 32(8): 2559-2578.
16	Baird J A, Taylor L S. Evaluation of amorphous solid dispersion properties using thermal analysis techniques[J]. Advanced Drug Delivery Reviews, 2012, 64(5): 396-421.
17	Schram C J, Smyth R J, Taylor L S, et al. Understanding crystal growth kinetics in the absence and presence of a polymer using a rotating disk apparatus[J]. Crystal Growth & Design, 2016, 16(5): 2640-2645.
18	Schram C J, Taylor L S, Beaudoin S P. Influence of polymers on the crystal growth rate of felodipine: correlating adsorbed polymer surface coverage to solution crystal growth inhibition[J]. Langmuir, 2015, 31(41): 11279-11287.
19	Ishizuka Y, Ueda K, Okada H, et al. Effect of drug-polymer interactions through HPMC-AS substituents on the physical stability of solid dispersions studied by FTIR and solid-state NMR[J]. Molecular Pharmaceutics, 2019, 16(6): 2785-2794.
20	Bhardwaj S P, Arora K K, Kwong E, et al. Mechanism of amorphous itraconazole stabilization in polymer solid dispersions: role of molecular mobility[J]. Molecular Pharmaceutics, 2014, 11(11): 4228-4237.
21	时念秋, 张勇, 冯波, 等. 通过溶解度法研究纤维素类聚合物抑制超饱和非洛地平结晶的特征[J]. 中国医院药学杂志, 2016, 36(24): 2152-2156.
	Shi N Q, Zhang Y, Feng B, et al. Investigation on inhibition of cellulose polymers against supersaturated felodipine crystallization by solubility method[J]. Chinese Journal of Hospital Pharmacy, 2016, 36(24): 2152-2156.
22	Arioglu-Tuncil S, Bhardwaj V, Taylor L S, et al. Amorphization of thiamine chloride hydrochloride: a study of the crystallization inhibitor properties of different polymers in thiamine chloride hydrochloride amorphous solid dispersions[J]. Food Research International, 2017, 99: 363-374.
23	Paus R, Hart E, Ji Y H, et al. Solubility and caloric properties of cinnarizine[J]. Journal of Chemical & Engineering Data, 2015, 60(8): 2256-2261.
24	Sunagawa I. Crystals: Growth, Morphology, and Perfection[M]. Cambridge: Cambridge University Press, 2007: 43-46.
25	Roberts K J, Docherty R, Tamura R. Engineering Crystallography: from Molecule to Crystal to Functional Form[M]. Netherlands: Springer, 2017.
26	Weng J, Huang Y, Hao D, et al. Recent advances of pharmaceutical crystallization theories[J]. Chinese Journal of Chemical Engineering, 2020, 28(4): 935-948.
27	Ji Y, Lemberg M, Prudic A, et al. Modeling and analysis of dissolution of paracetamol/Eudragit ^® formulations[J]. Chemical Engineering Research & Design, 2017, 121: 22-31.
28	Maurer G, Prausnitz J M. On the derivation and extension of the UNIQUAC equation[J]. Fluid Phase Equilibria, 1978, 2(2): 91-99.
29	Wu D X, Ji Y H. Influence of polymeric excipients on the solubility of aspirin: experimental measurement and model prediction[J]. Fluid Phase Equilibria, 2019, 508: 112450.
30	Vera J H, Sayegh S G, Ratcliff G A. A quasi lattice-local composition model for the excess Gibbs free energy of liquid mixtures[J]. Fluid Phase Equilibria, 1977, 1(2): 113-135.
31	Paus R, Ji Y H, Braak F, et al. Dissolution of crystalline pharmaceuticals: experimental investigation and thermodynamic modeling[J]. Industrial & Engineering Chemistry Research, 2015, 54(2): 731-742.
32	Prudic A, Ji Y H, Sadowski G. Thermodynamic phase behavior of API/polymer solid dispersions[J]. Molecular Pharmaceutics, 2014, 11(7): 2294-2304.
33	李攀, 孔慧, 宋卓栋, 等. 甲醇-甲醛-聚甲氧基二甲醚三元体系汽液平衡[J]. 化工学报, 2020, 71: 7-14.
	Li P, Kong H, Song Z D, et al. Vapor-liquid equilibrium for methanol-formaldehyde-polyoxymethylene dimethyl ethers ternary system[J]. CIESC Journal, 2020, 71: 7-14.
34	Jakob A, Joh R, Rose C, et al. Solid-liquid equilibria in binary mixtures of organic compounds[J]. Fluid Phase Equilibria, 1995, 113(1/2): 117-126.
35	Fu D, Zhang P, Du L X, et al. Experiment and model for the viscosities of MEA-PEG400, DEA-PEG400 and MDEA-PEG400 aqueous solutions[J]. Journal of Chemical Thermodynamics, 2014, 78: 109-113.
36	Venkatramanan K, Padmanaban R, Acoustic Arumugam V., thermal and molecular interactions of polyethylene glycol (2000, 3000, 6000)[C]//Proceedings of the 2015 ICU International Congress on Ultrasonics. 2015: 1052-1056.
37	Bolten D, Turk M. Experimental study on the surface tension, density, and viscosity of aqueous poly(vinylpyrrolidone) solutions[J]. Journal of Chemical & Engineering Data, 2011, 56(3): 582-588.
38	Matsuda H, Mori K, Tomioka M, et al. Determination and prediction of solubilities of active pharmaceutical ingredients in selected organic solvents[J]. Fluid Phase Equilibria, 2015, 406: 116-123.

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

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

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

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

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