拉莫三嗪-邻苯二甲酰亚胺药物共晶在有机溶剂中溶解度及三元相图测定

doi:10.11949/0438-1157.20190712

化工学报 ›› 2019, Vol. 70 ›› Issue (11): 4153-4161.DOI: 10.11949/0438-1157.20190712

拉莫三嗪-邻苯二甲酰亚胺药物共晶在有机溶剂中溶解度及三元相图测定

张金彦¹(),匡雯婕¹,吉绍长²,曹小雪¹,廖安平¹,蓝平¹()

1. 广西民族大学化学化工学院，广西多糖材料与改性重点实验室，广西高校化学与生物转化过程新技术重点实验室，广西南宁530006
2. 广西烟草专卖局，广西南宁 530006

收稿日期:2019-06-24 修回日期:2019-08-15 出版日期:2019-11-05 发布日期:2019-11-05
通讯作者: 蓝平
作者简介:张金彦（1984—），女，博士，副教授，zjy_03@126.com
基金资助:
国家自然科学基金项目(21606056);广西自然科学基金项目(2017GXNSFAA198091);广西生物多糖分离纯化及改性研究平台建设项目(桂科ZY18076005);广西民族大学相思湖创新团队项目(2016);广西民族大学研究生教育创新计划项目(gxun-chxps201817)

Determination of solubility and ternary phase diagram of lamotrigine-phthalimide pharmaceutical cocrystal in pure solvent

Jinyan ZHANG¹(),Wenjie KUANG¹,Shaochang JI²,Xiaoxue CAO¹,Anping LIAO¹,Ping LAN¹()

1. Guangxi Key Laboratory for Polysaccharide Materials and Modification, Key Laboratory of Chemical and Biological Transformation Process of Guangxi Higher Education Institutes, College of Chemistry and Chemical Engineering, Guangxi University for Nationalities, Nanning 530006, Guangxi, China
2. Guangxi Tobacco Monopoly Bureau, Nanning 530006, Guangxi, China

Received:2019-06-24 Revised:2019-08-15 Online:2019-11-05 Published:2019-11-05
Contact: Ping LAN

摘要/Abstract

摘要：

采用静态法测定了拉莫三嗪在正丙醇、异丙醇、正丁醇、异丁醇、丙酸乙酯、乙酸甲酯6种溶剂中的热力学行为，并采用Apelblat方程和λh方程进行了关联，其结果表明拉莫三嗪的溶解度随着温度的升高而升高，溶解行为由低到高为正丁醇>正丙醇>异丁醇>异丙醇，乙酸甲酯>丙酸乙酯，应用的方程拟合度较好，可用于单体拉莫三嗪热力学行为的预测。在此基础上，采用溶液法制备拉莫三嗪-邻苯二甲酰亚胺共晶，在298.15、303.15 K时，建立了共晶体在异丁醇、丙酸乙酯溶剂中的三元相图，结果表明同一溶剂体系内，随着温度的升高，拉莫三嗪-邻苯二甲酰亚胺共晶区域增大，有利于共晶的形成。同一温度下，拉莫三嗪-邻苯二甲酰亚胺共晶在异丁醇体系的对称性优于丙酸乙酯体系，表明拉莫三嗪-邻苯二甲酰亚胺共晶更易于在异丁醇体系中获得。

关键词: 拉莫三嗪, 邻苯二甲酰亚胺, 药物共晶, 热力学, 相平衡, 溶解性

Abstract:

The solubilities of lamotrigine in n-propanol, isopropanol, n-butanol, isobutanol, ethyl propionate, methyl acetate were determined by the static method at a temperature range of 283.15 K to 323.15 K and correlated by Apelblat equation and λh equation. The results showed that the solubility of lamotrigine increased with the increase of temperature, and the solubility of n-butyl alcohol > n-propyl alcohol > isobutanol > isopropanol, methyl acetate > ethyl propionate. Apelblat equation had better fitting effect, which can be used to predict the thermodynamic behavior of lamotrigine monomer. On this basis, the lamotrigine-phthalimide cocrystal was presented and the ternary phase diagram of lamotrigine- phthalimide - solvent was established in isobutanol and ethyl propionate at 298.15 K and 303.15 K.The results showed that with the increase of temperature, the stability region for the pure lamotrigine - phthalimide cocrystal was increased, and the ternary phase diagram was symmetrical in isobutanol, which was conducived to cocrystal formed.

Key words: lamotrigine, phthalimide, pharmaceutical cocrystal, thermodynamics, phase equilibria, solubility

中图分类号:

O 645

张金彦, 匡雯婕, 吉绍长, 曹小雪, 廖安平, 蓝平. 拉莫三嗪-邻苯二甲酰亚胺药物共晶在有机溶剂中溶解度及三元相图测定[J]. 化工学报, 2019, 70(11): 4153-4161.

Jinyan ZHANG, Wenjie KUANG, Shaochang JI, Xiaoxue CAO, Anping LIAO, Ping LAN. Determination of solubility and ternary phase diagram of lamotrigine-phthalimide pharmaceutical cocrystal in pure solvent[J]. CIESC Journal, 2019, 70(11): 4153-4161.

图/表 11

参考文献 34

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Solvent	T/K	x^exp×10³	x^cal×10³(Apelblat)	x^ca×10³ (λh)
isobutanol	283.15	0.5193	0.5849	0.5401
	288.15	0.7566	0.7510	0.7026
	293.15	0.8617	0.9503	0.9058
	298.15	1.3346	1.1859	1.1579
	303.15	1.5546	1.4609	1.4685
	308.15	1.7576	1.7776	1.8485
	313.15	2.0784	2.1380	2.3101
	318.15	2.4301	2.5433	2.8675
	323.15	3.0794	2.9941	3.5365
n-butyl alcohol	283.15	1.4601	1.4496	1.4417
	288.15	1.6682	1.6679	1.6739
	293.15	1.8872	1.9185	1.9349
	298.15	2.2309	2.2060	2.2273
	303.15	2.5958	2.5356	2.5541
	308.15	2.7752	2.9130	2.9183
	313.15	3.3956	3.3449	3.3234
	318.15	3.8945	3.8387	3.7730
	323.15	4.3699	4.4030	4.2712
n-propyl alcohol	283.15	1.0406	0.9781	1.0198
	288.15	1.2281	1.2437	1.2525
	293.15	1.4365	1.5542	1.5280
	298.15	1.9513	1.9108	1.8522
	303.15	2.2520	2.3135	2.2319
	308.15	2.7390	2.7607	2.6742
	313.15	3.3775	3.2497	3.1873
	318.15	3.6322	3.7764	3.7798
	323.15	4.3317	4.3354	4.4616
ethyl propionate	283.15	0.5773	0.5804	0.5867
	288.15	0.6544	0.6525	0.6520
	293.15	0.7394	0.7288	0.7228
	298.15	0.8150	0.8088	0.7995
	303.15	0.8622	0.8924	0.8826
	308.15	0.9753	0.9791	0.9724
	313.15	1.0975	1.0686	1.0695
	318.15	1.1540	1.1605	1.1745
	323.15	1.2507	1.2543	1.2880
methyl acetate	283.15	0.7791	0.7088	0.7763
	288.15	0.9716	0.9598	0.9772
	293.15	1.1703	1.2576	1.2206
	298.15	1.5689	1.5977	1.5137
	303.15	1.9761	1.9720	1.8644
	308.15	2.4009	2.3685	2.2814
	313.15	2.8242	2.7730	2.7747
	318.15	3.1267	3.1693	3.3552
	323.15	3.5420	3.5411	4.0352
isopropanol	283.15	0.3764	0.3596	0.3653
	288.15	0.4682	0.4659	0.4727
	293.15	0.5350	0.6007	0.6063
	298.15	0.8172	0.7710	0.7713
	303.15	1.0033	0.9853	0.9737
	308.15	1.2201	1.2539	1.2202
	313.15	1.6317	1.5891	1.5184
	318.15	1.9682	2.0059	1.8771
	323.15	2.5341	2.5224	2.3061

Solvent	T/K	x^exp×10³	x^cal×10³(Apelblat)	x^ca×10³ (λh)
isobutanol	283.15	0.5193	0.5849	0.5401
	288.15	0.7566	0.7510	0.7026
	293.15	0.8617	0.9503	0.9058
	298.15	1.3346	1.1859	1.1579
	303.15	1.5546	1.4609	1.4685
	308.15	1.7576	1.7776	1.8485
	313.15	2.0784	2.1380	2.3101
	318.15	2.4301	2.5433	2.8675
	323.15	3.0794	2.9941	3.5365
n-butyl alcohol	283.15	1.4601	1.4496	1.4417
	288.15	1.6682	1.6679	1.6739
	293.15	1.8872	1.9185	1.9349
	298.15	2.2309	2.2060	2.2273
	303.15	2.5958	2.5356	2.5541
	308.15	2.7752	2.9130	2.9183
	313.15	3.3956	3.3449	3.3234
	318.15	3.8945	3.8387	3.7730
	323.15	4.3699	4.4030	4.2712
n-propyl alcohol	283.15	1.0406	0.9781	1.0198
	288.15	1.2281	1.2437	1.2525
	293.15	1.4365	1.5542	1.5280
	298.15	1.9513	1.9108	1.8522
	303.15	2.2520	2.3135	2.2319
	308.15	2.7390	2.7607	2.6742
	313.15	3.3775	3.2497	3.1873
	318.15	3.6322	3.7764	3.7798
	323.15	4.3317	4.3354	4.4616
ethyl propionate	283.15	0.5773	0.5804	0.5867
	288.15	0.6544	0.6525	0.6520
	293.15	0.7394	0.7288	0.7228
	298.15	0.8150	0.8088	0.7995
	303.15	0.8622	0.8924	0.8826
	308.15	0.9753	0.9791	0.9724
	313.15	1.0975	1.0686	1.0695
	318.15	1.1540	1.1605	1.1745
	323.15	1.2507	1.2543	1.2880
methyl acetate	283.15	0.7791	0.7088	0.7763
	288.15	0.9716	0.9598	0.9772
	293.15	1.1703	1.2576	1.2206
	298.15	1.5689	1.5977	1.5137
	303.15	1.9761	1.9720	1.8644
	308.15	2.4009	2.3685	2.2814
	313.15	2.8242	2.7730	2.7747
	318.15	3.1267	3.1693	3.3552
	323.15	3.5420	3.5411	4.0352
isopropanol	283.15	0.3764	0.3596	0.3653
	288.15	0.4682	0.4659	0.4727
	293.15	0.5350	0.6007	0.6063
	298.15	0.8172	0.7710	0.7713
	303.15	1.0033	0.9853	0.9737
	308.15	1.2201	1.2539	1.2202
	313.15	1.6317	1.5891	1.5184
	318.15	1.9682	2.0059	1.8771
	323.15	2.5341	2.5224	2.3061

Solvent	A	B	C	R²	RAD×10²	RMSD×10⁵
isobutanol	144.63	-9988.48	-20.69	0.9841	0.0580	7.22
ethyl propionate	58.70	-4460.85	-8.93	0.9939	0.0116	1.46
n-butyl alcohol	-99.34	2041.09	15.16	0.9949	0.0161	5.47
methyl acetate	517.02	-26699.35	-76.16	0.9968	0.0270	4.38
n-propyl alcohol	212.50	-12743.95	-30.89	0.9927	0.0321	6.68
isopropanol	-85.47	-256.36	13.89	0.9965	0.0360	3.34

Solvent	A	B	C	R²	RAD×10²	RMSD×10⁵
isobutanol	144.63	-9988.48	-20.69	0.9841	0.0580	7.22
ethyl propionate	58.70	-4460.85	-8.93	0.9939	0.0116	1.46
n-butyl alcohol	-99.34	2041.09	15.16	0.9949	0.0161	5.47
methyl acetate	517.02	-26699.35	-76.16	0.9968	0.0270	4.38
n-propyl alcohol	212.50	-12743.95	-30.89	0.9927	0.0321	6.68
isopropanol	-85.47	-256.36	13.89	0.9965	0.0360	3.34

Solvent	λ	h	R²	RAD×10²	RMSD×10⁵
isobutanol	0.3338	12835.36	0.9781	0.0935	23.71
ethyl propionate	0.0054	287329.59	0.9937	0.0179	2.01
n-butyl alcohol	0.0487	48581.73	0.9958	0.0206	7.79
methyl acetate	0.2125	17614.98	0.9943	0.0471	19.16
n-propyl alcohol	0.1503	22170.43	0.9921	0.0349	10.47
isopropanol	0.1979	21212.88	0.9852	0.0515	9.50

拉莫三嗪-邻苯二甲酰亚胺药物共晶在有机溶剂中溶解度及三元相图测定

Determination of solubility and ternary phase diagram of lamotrigine-phthalimide pharmaceutical cocrystal in pure solvent

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Composition of liquid phase at 298.15 K				Composition of liquid phase at 303.15 K
LAM	PLT	Isobutanol	Equilibrium solid phase	LAM	PLT	Isobutanol	Equilibrium solid phase
0	0.00388	0.99612	PTL	0	0.00499	0.99501	PTL
0.00091	0.00403	0.99506	PTL	0.00085	0.00500	0.99415	PTL
0.00132	0.00422	0.99446	PTL	0.00113	0.00505	0.99382	PTL
0.00144	0.00418	0.99439	PTL	0.00143	0.00488	0.99369	PTL
0.00195	0.00411	0.99394	PTL+1∶1LAM/PTL	0.00233	0.00461	0.99307	PTL+1∶1LAM/PTL
0.0037	0.00215	0.99414	1∶1LAM/PTL	0.00292	0.00390	0.99318	1∶1LAM/PTL
0.00445	0.00185	0.99370	LAM+1∶1LAM/PTL	0.00404	0.00243	0.99353	1∶1LAM/PTL
0.00468	0.00148	0.99385	LAM	0.00521	0.00222	0.99257	LAM+1∶1LAM/PTL
0.00455	0.00114	0.99431	LAM	0.00539	0.00112	0.99349	LAM
0.00453	0.00097	0.99450	LAM	0.00546	0.00147	0.99307	LAM
0.0046	0	0.99540	LAM	0.00535	0	0.99465	LAM

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Composition of liquid phase at 298.15 K				Composition of liquid phase at 303.15 K
LAM	PLT	Ethyl propionate	Equilibrium solid phase	LAM	PLT	Ethyl propionate	Equilibrium solid phase
0	0.00867	0.99133	PTL	0	0.00987	0.99013	PTL
0.00086	0.00844	0.99070	PTL	0.001	0.00920	0.9898	PTL
0.00102	0.00854	0.99044	PTL	0.00121	0.00943	0.98935	PTL
0.00103	0.00874	0.99023	PTL+1∶1LAM/PTL	0.00119	0.00958	0.98923	PTL+1∶1LAM/PTL
0.00128	0.00743	0.99129	1∶1LAM/PTL	0.00125	0.00752	0.99123	1∶1LAM/PTL
0.00165	0.00550	0.99284	1∶1LAM/PTL	0.00195	0.00559	0.99246	1∶1LAM/PTL
0.00238	0.00387	0.99374	LAM+1∶1LAM/PTL	0.00247	0.00441	0.99312	LAM+1∶1LAM/PTL
0.00211	0.00136	0.99653	LAM	0.00226	0.00148	0.99625	LAM
0.00214	0.00122	0.99664	LAM	0.00242	0.00121	0.99637	LAM
0.00213	0.00100	0.99687	LAM	0.00232	0.00098	0.99670	LAM
0.00214	0.00080	0.99706	LAM	0.00233	0.00081	0.99686	LAM
0.00204	0	0.99796	LAM	0.00216	0	0.99784	LAM

Composition of liquid phase at 298.15 K				Composition of liquid phase at 303.15 K
LAM	PLT	Ethyl propionate	Equilibrium solid phase	LAM	PLT	Ethyl propionate	Equilibrium solid phase
0	0.00867	0.99133	PTL	0	0.00987	0.99013	PTL
0.00086	0.00844	0.99070	PTL	0.001	0.00920	0.9898	PTL
0.00102	0.00854	0.99044	PTL	0.00121	0.00943	0.98935	PTL
0.00103	0.00874	0.99023	PTL+1∶1LAM/PTL	0.00119	0.00958	0.98923	PTL+1∶1LAM/PTL
0.00128	0.00743	0.99129	1∶1LAM/PTL	0.00125	0.00752	0.99123	1∶1LAM/PTL
0.00165	0.00550	0.99284	1∶1LAM/PTL	0.00195	0.00559	0.99246	1∶1LAM/PTL
0.00238	0.00387	0.99374	LAM+1∶1LAM/PTL	0.00247	0.00441	0.99312	LAM+1∶1LAM/PTL
0.00211	0.00136	0.99653	LAM	0.00226	0.00148	0.99625	LAM
0.00214	0.00122	0.99664	LAM	0.00242	0.00121	0.99637	LAM
0.00213	0.00100	0.99687	LAM	0.00232	0.00098	0.99670	LAM
0.00214	0.00080	0.99706	LAM	0.00233	0.00081	0.99686	LAM
0.00204	0	0.99796	LAM	0.00216	0	0.99784	LAM