舒巴坦钠溶析结晶工艺优化

doi:10.16085/j.issn.1000-6613.2018-2126

摘要/Abstract

摘要：

目前舒巴坦钠粗品的提纯采用还原成舒巴坦酸后再经反应结晶合成舒巴坦钠的方式，耗时耗力且所需药品、试剂种类较多，不节能环保。针对该问题，采用正交实验 $L 27 313$ 对舒巴坦钠的溶析结晶工艺进行优化，探明了6个因素6个交互作用对粒度、纯度以及两者的综合评分的影响，包括养晶时间（A）、溶析剂用量（B）、溶析剂中乙醇的体积分数（C）、溶析剂的滴加速率（D）、搅拌速率（E）、温度（F）以及养晶时间分别与溶析剂用量（A×B）、与溶析剂中乙醇的体积分数（A×C）的交互作用、溶析剂用量与溶析剂中乙醇的体积分数的交互作用（B×C），并得到了一组最优方案A ₂ B ₂ C ₁ D ₃ E ₃ F ₂。通过该方案可获得纯度x>97%，体积平均粒度D[4,3]≈290μm，质量收率约为84%的舒巴坦钠产品，并发现杂质舒巴坦青霉胺对舒巴坦钠的粒度分布有一定的影响。在解决原有问题的基础上，合适粒度分布的舒巴坦钠产品也可为后续制剂工艺提供方便。

关键词: 舒巴坦钠, 溶析结晶, 正交实验, 纯度, 晶体粒度分布

Abstract:

At present, the way of purifying sulbactam sodium is to synthesize sulbactam sodium by sulbactam acid, which is obtained by reduction reaction. The method is time-consuming, labor-intensive and requires a large variety of drugs and reagents, and is not energy-saving and environmentally friendly. For this problem, the orthogonal experiment $L 27 313$ was used to optimize the anti-solvent crystallization of sulbactam sodium. The effects of six factors and three interactions on crystal size distribution, purity and comprehensive scores of the two were considered, included aging time (A), volume of anti-solvent used(B), volume fraction of ethanol in the anti-solvent(C), rate of addition of the anti-solvent (D), stirring rate (E), crystallization temperature(F), and the interaction between the aging time and the volume of the anti-solvent (A×B), the interaction between the aging time and the volume fraction of ethanol in the decanting agent (A×C), the interaction between the volume of the anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C) . The results of variance analysis showed: the used volume of anti-solvent (B) has the most significant effect on crystal size distribution(CSD), but other factors and interactions are not significant; the volume fraction of ethanol in the anti-solvent(C), the dropping rate of the anti-solvent(D), the stirring rate (E) and the interaction between the aging time and the volume fraction of ethanol in the anti-solvent(A×C) have a highly significant impact on the purity, and both of interaction between the crystallization time and the volume of the anti-solvent(A×B), and the interaction between the volume of anti-solvent used and the volume fraction of ethanol in the anti-solvent(B×C) have a significant effect, but the others are not significant; when the significant level α is between 0.10 and 0.025, considering the purity-CSD at a ratio of 70% and 30% respectively, volume of the anti-solvent used(B) and the volume fraction of ethanol in the anti-solvent(C) are highly significant, and others are not significant. The optimal operating level combination is A ₂ B ₂ C ₁ D ₃ E ₃ F ₂. Repeated validation tests yielded: the purity of sulbactam sodium raw material can be increased from 79.58% to over 97% by only once anti-solvent crystallization, and the crystal size distribution D[4,3] can be increased from 41.1μm to above 290μm. The mass fraction yield of sulbactam sodium obtained by multiple confirmatory experiments is about 84%. It is found that the impurity sulbactam penicillamine has a certain influence on the particle size distribution of sulbactam sodium. On the basis of solving the original problems, the sulbactam sodium product with suitable particle size distribution can also provide convenience for the subsequent preparation process.

Key words: sulbactam sodium, anti-solvent crystallization, orthogonal test, purity, crystal size distribution

中图分类号:

TQ028

李丽, 刘宝树, 郑学明, 孙华. 舒巴坦钠溶析结晶工艺优化[J]. 化工进展, 2019, 38(06): 2905-2914.

Li LI, Baoshu LIU, Xueming ZHENG, Hua SUN. Optimization of anti-solvent crystallization process of sulbactam sodium[J]. Chemical Industry and Engineering Progress, 2019, 38(06): 2905-2914.

图/表 18

图1 舒巴坦钠结构式

图2 结晶实验装置

表1 因素与水平表

水平

养晶时间

溶析剂

用量/mL

溶析剂中乙醇的体积分数/%

滴加速率

/mL·min^-1

搅拌速度

/r·min^-1

温度/℃

表2 设计及实验结果

序号	A	B	A×B	A×B	C	A×C	A×C	B×C	D	空白	B×C	E	F	D[4,3]/μm	x/%	综合评分
1	1	1	1	1	1	1	1	1	1	1	1	1	1	77.50	99.1576	76.74
2	1	1	1	1`	2	2	2	2	2	2	2	2	2	125.00	95.3440	78.18
3	1	1	1	1	3	3	3	3	3	3	3	3	3	21.70	97.1945	70.50
4	1	2	2	2	1	1	1	2	2	2	3	3	3	145.00	99.0681	82.55
5	1	2	2	2	2	2	2	3	3	3	1	1	1	135.00	94.0519	78.13
6	1	2	2	2	3	3	3	1	1	1	2	2	2	158.00	93.9219	80.04
7	1	3	3	3	1	1	1	3	3	3	2	2	2	141.00	98.6865	81.93
8	1	3	3	3	2	2	2	1	1	1	3	3	3	183.00	96.4820	84.02
9	1	3	3	3	3	3	3	2	2	2	1	1	1	174.00	94.6185	81.93
10	2	1	2	3	1	2	3	1	2	3	1	2	3	178.00	94.3386	82.08
11	2	1	2	3	2	3	1	2	3	1	2	3	1	114.00	99.1497	79.91
12	2	1	2	3	3	1	2	3	1	2	3	1	2	64.90	96.1809	73.54
13	2	2	3	1	1	2	3	2	3	1	3	1	2	345.00	98.8351	99.77
14	2	2	3	1	2	3	1	3	1	2	1	2	3	142.00	96.2244	80.28
15	2	2	3	1	3	1	2	1	2	3	2	3	1	138.00	96.5311	80.15
16	2	3	1	2	1	2	3	3	1	2	2	3	1	205.00	98.9170	87.66
17	2	3	1	2	2	3	1	1	2	3	3	1	2	181.00	94.5988	82.52
18	2	3	1	2	3	1	2	2	3	1	1	2	3	140.00	97.5186	81.02
19	3	1	3	2	1	3	2	1	3	2	1	3	2	164.00	99.0285	84.17
20	3	1	3	2	2	1	3	2	1	3	2	1	3	95.40	95.7996	75.93
21	3	1	3	2	3	2	1	3	2	1	3	2	1	147.00	94.7566	79.68
22	3	2	1	3	1	3	2	2	1	3	3	2	1	159.00	98.9166	83.66
23	3	2	1	3	2	1	3	3	2	1	1	3	2	218.00	94.5893	85.73
24	3	2	1	3	3	2	1	1	3	2	2	1	3	125.00	97.4810	79.69
25	3	3	2	1	1	3	2	3	2	1	2	1	3	185.00	94.2366	82.61
26	3	3	2	1	2	1	3	1	3	2	3	2	1	216.00	93.9306	85.09
27	3	3	2	1	3	2	1	2	1	3	1	3	2	110.00	97.5640	78.44

图3 不同溶剂中的舒巴坦钠晶体产品的X射线粉末衍射图

表3 粒度D[4,3]的实验结果计算表[33]

因素	$K 1 j ˉ$	$K 2 j ˉ$	$K 3 j ˉ$	$S j$
A	128.91	167.54	157.711	7256.007
B	109.72	173.89	170.556	23487.500
A×B	139.13	145.100	169.93	4802.807
A×B	151.133	152.27	150.77	11.007
C	177.72	156.600	119.844	15440.869
A×C	137.311	172.556	144.300	6268.176
A×C	131.39	143.767	179.011	10989.769
B×C	157.833	156.378	139.96	1774.269
D	132.756	165.667	155.744	5130.242
空白	174.167	151.211	128.79	9266.569
B×C	148.722	142.93	162.511	1820.802
E	153.644	156.222	144.300	708.309
F	151.722	167.43	135.011	4731.902

表3 粒度D[4,3]的实验结果计算表[33]

因素	$K 1 j ˉ$	$K 2 j ˉ$	$K 3 j ˉ$	$S j$
A	128.91	167.54	157.711	7256.007
B	109.72	173.89	170.556	23487.500
A×B	139.13	145.100	169.93	4802.807
A×B	151.133	152.27	150.77	11.007
C	177.72	156.600	119.844	15440.869
A×C	137.311	172.556	144.300	6268.176
A×C	131.39	143.767	179.011	10989.769
B×C	157.833	156.378	139.96	1774.269
D	132.756	165.667	155.744	5130.242
空白	174.167	151.211	128.79	9266.569
B×C	148.722	142.93	162.511	1820.802
E	153.644	156.222	144.300	708.309
F	151.722	167.43	135.011	4731.902

图4 因素与指标关系图

表4 粒度的方差分析

方差来源	S_j	f	$S j ˉ$	F_j	F-theory	显著性
A	7256.007	2	3628.003	1.84	2.62-3.54-4.56
B	23487.500	2	11743.750	5.95		**
C	15440.869	2	7720.434	3.91		*
D ^△	5130.242	2	2565.121	1.30
E ^△	708.309	2	354.154	0.18
F ^△	4731.902	2	2365.951	1.20
A×B ^△	4813.813	4	1203.453	0.61	2.29-2.93-3.61
A×C	17257.944	4	4314.486	2.19
B×C ^△	3595.071	4	898.768	0.46
e	9266.569	2	4633.284	2.35
$e Δ$	35501.913	18	1972.329

表4 粒度的方差分析

方差来源	S_j	f	$S j ˉ$	F_j	F-theory	显著性
A	7256.007	2	3628.003	1.84	2.62-3.54-4.56
B	23487.500	2	11743.750	5.95		**
C	15440.869	2	7720.434	3.91		*
D ^△	5130.242	2	2565.121	1.30
E ^△	708.309	2	354.154	0.18
F ^△	4731.902	2	2365.951	1.20
A×B ^△	4813.813	4	1203.453	0.61	2.29-2.93-3.61
A×C	17257.944	4	4314.486	2.19
B×C ^△	3595.071	4	898.768	0.46
e	9266.569	2	4633.284	2.35
$e Δ$	35501.913	18	1972.329

表5 纯度的实验结果计算表

因素	$K 1 j ˉ$	$K 2 j ˉ$	$K 3 j ˉ$	$S j$
A	96.50	96.92	96.26	2.039
B	96.77	96.62	96.28	1.130
A×B	97.08	95.83	96.77	7.678
A×B	96.56	96.41	96.72	0.430
C	97.91	95.57	96.20	26.319
A×C	96.83	96.42	96.43	0.978
A×C	97.41	96.48	95.79	11.842
B×C	96.16	97.42	96.09	10.094
D	97.02	95.34	97.32	20.426
空白	96.52	96.75	96.41	0.564
B×C	96.34	96.67	96.66	0.634
E	96.11	95.96	97.61	15.087
F	96.67	96.53	96.48	0.172

表5 纯度的实验结果计算表

因素	$K 1 j ˉ$	$K 2 j ˉ$	$K 3 j ˉ$	$S j$
A	96.50	96.92	96.26	2.039
B	96.77	96.62	96.28	1.130
A×B	97.08	95.83	96.77	7.678
A×B	96.56	96.41	96.72	0.430
C	97.91	95.57	96.20	26.319
A×C	96.83	96.42	96.43	0.978
A×C	97.41	96.48	95.79	11.842
B×C	96.16	97.42	96.09	10.094
D	97.02	95.34	97.32	20.426
空白	96.52	96.75	96.41	0.564
B×C	96.34	96.67	96.66	0.634
E	96.11	95.96	97.61	15.087
F	96.67	96.53	96.48	0.172

表6 纯度的方差分析表

方差来源	S	f	$S ˉ$	F_j	F-theory	显著性
A	2.039	2	1.019	3.28	5.14-7.26-10.90
B^△	1.130	2	0.565
C	26.319	2	13.160	42.32		**
D	20.426	2	10.213	32.84		**
E	15.087	2	7.543	24.26		**
F^△	0.172	2	0.086
A×B	8.108	4	2.027	6.52	4.53-6.23-9.15	*
A×C	12.820	4	3.205	10.31		**
B×C	10.727	4	2.682	8.62		*
e	0.546	2	0.282
$e Δ$	1.866	6	0.311

表6 纯度的方差分析表

方差来源	S	f	$S ˉ$	F_j	F-theory	显著性
A	2.039	2	1.019	3.28	5.14-7.26-10.90
B^△	1.130	2	0.565
C	26.319	2	13.160	42.32		**
D	20.426	2	10.213	32.84		**
E	15.087	2	7.543	24.26		**
F^△	0.172	2	0.086
A×B	8.108	4	2.027	6.52	4.53-6.23-9.15	*
A×C	12.820	4	3.205	10.31		**
B×C	10.727	4	2.682	8.62		*
e	0.546	2	0.282
$e Δ$	1.866	6	0.311

表7 因素A,C的二元表

项目	C ₁	C ₂	C ₃	K_iA	a_i
A ₁	D ₁₁=296.91	D ₁₂=285.88	D ₁₃=285.73	868.53	-0.06
A ₂	D ₂₁=292.09	D ₂₂=289.97	D ₂₃=290.23	872.29	0.36
A ₃	D ₃₁=292.18	D ₃₂=284.32	D ₃₃=289.80	866.30	-0.30
K_iC	881.18	860.17	865.77	2607.12
c_j	1.35	-0.99	-0.36

表8 纯度的 a c i j 值表

项目	C ₁	C ₂	C ₃
A ₁	1.21	-0.22	-0.89
A ₂	-0.91	0.72	0.19
A ₃	-0.21	-0.50	0.71

表9 因素B,C的二元表

项目	C ₁	C ₂	C ₃	K_iB	b_i
B ₁	292.52	290.29	288.13	870.95	0.21
B ₂	296.82	284.87	287.93	869.62	0.06
B ₃	291.84	285.01	289.70	866.55	-0.28
K_iC	881.18	860.17	865.77	2607.12
c_j	1.35	-0.99	-0.36

表10 B,C交互作用 b c i j 表

项目	C ₁	C ₂	C ₃
B ₁	-0.61	0.98	-0.36
B ₂	0.97	-0.68	-0.28
B ₃	-0.35	-0.29	0.65

表11 综合评分的计算表

因素	$K 1 j ˉ$	$K 2 j ˉ$	$K 3 j ˉ$	$S j$
A	79.34	82.99	81.67	61.63
B	77.86	83.33	82.80	164.14
A×B	80.63	80.27	83.09	42.58
A×B	81.31	81.30	81.39	0.04
C	84.57	81.09	78.33	176.14
A×C	80.30	83.07	80.62	41.40
A×C	80.19	80.61	83.19	47.54
B×C	81.61	82.37	80.01	26.28
D	80.03	81.71	82.25	23.98
空白	83.28	81.45	79.26	72.98
B×C	80.95	80.68	82.37	14.92
E	81.21	81.33	81.46	0.28
F	81.44	82.70	79.85	36.73

表11 综合评分的计算表

因素	$K 1 j ˉ$	$K 2 j ˉ$	$K 3 j ˉ$	$S j$
A	79.34	82.99	81.67	61.63
B	77.86	83.33	82.80	164.14
A×B	80.63	80.27	83.09	42.58
A×B	81.31	81.30	81.39	0.04
C	84.57	81.09	78.33	176.14
A×C	80.30	83.07	80.62	41.40
A×C	80.19	80.61	83.19	47.54
B×C	81.61	82.37	80.01	26.28
D	80.03	81.71	82.25	23.98
空白	83.28	81.45	79.26	72.98
B×C	80.95	80.68	82.37	14.92
E	81.21	81.33	81.46	0.28
F	81.44	82.70	79.85	36.73

表12 综合评分的方差分析

方差来源	S	f	$S ˉ$	F _j	F-theory	显著性
A $Δ$	61.63	2	30.82		2.62-3.54-4.56
B	164.14	2	82.07	5.29		*
C	176.14	2	88.07	5.67		*
D $Δ$	23.98	2	11.99
E $Δ$	0.28	2	0.14
F $Δ$	36.73	2	18.37
A×B $Δ$	42.62	4	10.65		2.29-2.93-3.61
A×C $Δ$	88.94	4	22.24	1.43		不显著
B×C $Δ$	41.20	4	10.30
e	72.98	2	36.49
$e Δ$	279.43	18	15.52

表12 综合评分的方差分析

方差来源	S	f	$S ˉ$	F _j	F-theory	显著性
A $Δ$	61.63	2	30.82		2.62-3.54-4.56
B	164.14	2	82.07	5.29		*
C	176.14	2	88.07	5.67		*
D $Δ$	23.98	2	11.99
E $Δ$	0.28	2	0.14
F $Δ$	36.73	2	18.37
A×B $Δ$	42.62	4	10.65		2.29-2.93-3.61
A×C $Δ$	88.94	4	22.24	1.43		不显著
B×C $Δ$	41.20	4	10.30
e	72.98	2	36.49
$e Δ$	279.43	18	15.52

图5 原料、产品与标准品的HPLC图

图6 原料、晶种、对照组及实验组粒度分布图

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