CN110693829B - 聚氧乙烯基Gemini非离子表面活性剂及其合成方法 - Google Patents
聚氧乙烯基Gemini非离子表面活性剂及其合成方法 Download PDFInfo
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- CN110693829B CN110693829B CN201911288529.7A CN201911288529A CN110693829B CN 110693829 B CN110693829 B CN 110693829B CN 201911288529 A CN201911288529 A CN 201911288529A CN 110693829 B CN110693829 B CN 110693829B
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- polyoxyethylene
- acid
- gemini
- nonionic surfactant
- surfactant
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Abstract
本发明公开了一种聚氧乙烯基Gemini非离子表面活性剂及其合成方法,其是由二‑不饱和脂肪酸烷基二醇二酯环氧化产物与聚乙二醇反应得到,这种表面活性剂结合了聚氧乙烯基表面活性剂的温和无刺激、易生物降解、环境友好的优点,还具备了Gemini表面活性剂的优异性能,实验证明相比于现有的注射用增溶辅料,本发明的致溶血作用明显减弱,具有更高的安全性,而增溶活性还有所提高,是一种生物相容性良好表面活性剂,可广泛应用于药用注射剂的增溶辅料,具有广阔的应用前景。
Description
技术领域
本发明涉及一种注射用药用增溶辅料的制备,确切地说是一种聚氧乙烯基Gemini非离子型表面活性剂及其合成方法。
背景技术
表面活性剂在水溶液中能形成胶束,并能定向吸附于两相界面上,降低界面(表面)张力,可起增溶、乳化、湿润、浸透和分散等多种作用,并且表面活性剂用量少(一般为百分之几到千分之几),被称为“工业味精”。广泛应用于医药、食品、化妆品等诸多领域。
在医药行业中,对于液体制剂特别是注射剂,为了增加难溶性药物成分的溶解度,必须加入以聚山梨酯80(Tween 80)为代表的表面活性剂作为增溶辅料,以改善主药的成药性、注射剂的澄明度及稳定性。一般认为这类非离子表面活性剂相对于阳离子、阴离子和两性表面活性剂是安全的,被广泛用于中药制剂、化学药物和生物制品的注射剂,在制药工业中具有重要的价值,各国药典对其均有收载。但随着各国对药品不良反应监测及报告制度的完善,近年来,临床上出现了大量严重的中药注射剂不良事件,国外也有由于Tween 80引起不良反应的报道,使得Tween 80质量及安全性的研究受到广泛关注。随着研究的不断深入,实验证明以Tween 80为代表的非离子表面活性剂并非完全惰性,仍有一定的毒性和药理作用,最主要的是对红细胞的稳定性的影响,可引发溶血、类过敏和休克等严重不良反应。而毒性的来源并非由于过氧化物、有机溶剂残留、油酸纯度等微量杂质所引发,而是来自于其自身主成份的结构特性。不同于化学药物可以通过成盐、结构改造等手段改善其水溶性,中药注射剂成分复杂,添加增溶辅料是保证其成药性的唯一手段,不解决增溶辅料的安全性问题,就不能解决中药注射剂的安全性问题。因此,设计合成安全性及增溶性优于Tween 80的新型表面活性剂是目前制药工业的急切需求。
Gemini型表面活性剂通常由连接基团将两个单基表面活性剂以化学键方式联接在一起而形成,其中连接基可以是柔性基团(如亚甲基、聚氧丙烯链),也可以是刚性基团(如苯、双键、叁键、三唑环、均二苯代己烯等)。与传统的表面活性剂相比,Gemini型表面活性剂与对应的普通表面活性剂相比,具有较低的临界胶束浓度(CMC)值,良好的增溶能力等。发明人在研究Tween 80中的化学组分中发现,Tween 80所含有的聚氧乙烯山梨醇酐二油酸酯相对于其他7类成分,具有良好的增溶能力及安全性(安全性能指数高),而其结构类似于非离子型Gemini表面活性剂。提示发明人可通过设计合成一类非离子型Gemini表面活性剂是解决目前增溶辅料引发的不良反应一条可行的途径。
目前,报道的非离子型Gemini表面活性剂主要有以下几类。
(1)聚氧乙烯型非离子Gemini表面活性剂。
公开号CN103446944A公开了以蓖麻油酸、顺丁烯二酸酐(丁二酸酐)或、聚乙二醇(600)为原料,首先采用硼酸酯法合成蓖麻油酸聚乙二醇硼酸酯(催化剂为对甲苯磺酸-PTS),再用酸酐作间隔基团连接蓖麻油酸聚乙二醇硼酸酯上的羟基(催化剂为PTS),形成双酯,最后将硼酸酯键水解,然后提纯,得到一种新型的、可降解的、具有Gemini类结构的表面活性剂。 结构如下。
公开号CN109678720A公开了以一种(辛基苯酚聚氧乙烯醚双取代)二甲酸二苯醚非离子型双子表面活性剂及其合成。由4,4′-二甲酸二苯醚进行酰氯化反应,得到4,4′-二甲酰氯二苯醚,再与辛基苯酚聚氧乙烯醚(OP-10)发生酯化反应制得非离子型Gemini表面活性剂(辛基苯酚聚氧乙烯醚双取代)二甲酸二苯醚。可作为用于三次采油中的碱/表面活性剂、驱油剂。结构如下。
公开号CN110156827A、CN110156594A、CN110105254A公开了三种聚氧乙烯醚酸(磷酸、羧酸、硫酸)Gemini表面活性剂类减阻剂及其制备方法和应用。结构如下。
(2)葡萄糖基非离子Gemini型表面活性剂。
公开号CN107673987B公开了以双(C8-C18长链烷基甘油醚)二胺与葡萄糖酸内酯反应得到,这种表面活性剂结合了糖基表面活性剂的温和无刺激、易生物降解、环境友好的优点,还具备了双子表面活性剂的优异性能,如进一步提高表面活性、降低临界胶束浓度等。结构如下。
本发明是为了解决注射剂增溶辅料的安全性问题而设计的Gemini型表面活性剂,为了减少表面活性剂与体内生物大分子间的静电亲和作用,所以表面活性剂的类型必须为非离子型表面活性剂。其次,所设计的表面活性剂必须可降解,分子量过大的,如公开号CN110156827A、CN110156594A、CN110105254A聚醚型表面活性剂不易被肾脏排泄,不适合注射剂的应用,同时其分子片段的亲水基团实际为酸根,实际应归类为阴离子表面活性剂,在体内碱性条件下易解离为阴离子,与体内多肽等碱基会发生亲电作用,生物相容性不佳。在安全性方面,如公开号CN107673987B以葡萄糖基为亲水链,降低表面张力的能力太强,可达25.6mN/m,而发明人研究发现表面张力大小与溶血性呈负相关,该类非离子型Gemini表面活性剂安全性不满足注射剂的要求。在增溶性方面,公开号CN109678720A所发明的表面活性剂亲酯性太强,可驱油,但不可溶于水,不能作为液体制剂的增溶辅料。从结构上看公开号CN103446944A中的聚氧乙烯型Gemini表面活性剂是最佳的结构设计,但发明人对其进行验证研究后发现其合成产物并不是如其结构图所示的单一产物。首先蓖麻油酸与PEG硼酸酯反应并不能仅得到蓖麻油酸的单PEG酯,也会生成二酯,硼酸对PEG没有封端作用;其次丁(烯)二酸酐与蓖麻油酸的单PEG酯反应,由于蓖麻油酸单PEG酯有两个游离羟基,不仅仅产生如其结构图所示的Gemini的二元产物,还有产生复杂的三元、四元、五元产物,而且反应位点不局限于蓖麻油酸的12位羟基上、也存在于PEG端的游离羟基,因此产物组成非常复杂,和Tween 80一样是一个混合物。而对于药用辅料而言,如此复杂的混合物难以进行质量控制,而单一成分是更优的选择。基于以上的安全性、增溶性、质量可控性的考虑,本发明重新设计了合成路线,以二元醇和不饱和脂肪酸酯化,以达到增长亲酯链的目的,同时酯键在体内可以水解,以达到生物相容性满足注射剂使用的要求,合成中间体的双键经过环氧化活化后与亲水端(聚乙二醇)连接制备得到一种新型的聚氧乙烯基非离子型Gemini表面活性剂。经过纯度、物性、增溶性及安全性测试,可优选出相比Tween 80增溶性及安全性更好的表面活性剂,用于医药工业的使用。
发明内容
本发明的目的在于提供一种聚氧乙烯基Gemini非离子表面活性剂及其合成方法。
本发明的技术方案如下。
一种聚氧乙烯基Gemini非离子表面活性剂,其特征在于,其结构式如下所示。
其中,a为C2~C18烷基,b,c,d,f为C0~C8烷基;n为6~50的自然数。
所述的a优选C12烷基,b,c,d,f优选C7烷基,所述的n优选20~24。
所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于,包括以下三个步骤。
步骤一、二-不饱和脂肪酸烷基二醇二酯的合成:在加装有分水器的三颈烧瓶加入不饱和脂肪酸、烷基二醇和酸性催化剂,以苯/甲苯/二甲苯为带水剂,在氮气保护下,回流反应2~10 h。冷却至室温后,减压抽滤,滤液在旋转蒸发仪上减压除去溶剂甲苯得到粗产物,反应方程式如下,其中a为C2~C18烷基,b,c,d,f为C0~C8烷基。
步骤二、将二-不饱和脂肪酸烷基二醇二酯溶于二氯甲烷中,分步添加2~2.3倍摩尔量的间氯过氧苯甲酸,室温搅拌24~72 h,过滤,滤液添加适量亚硫酸钠和碳酸氢钠还原中和未反应的间氯过氧苯甲酸,过滤,滤液经旋转蒸发仪减压除去二氯甲烷,得到粗品,上硅胶柱,用石油醚-乙酸乙酯洗脱后得二-环氧烷酸烷基二酯,反应方程式如下,其中其中a为C2~C18烷基,b,c,d,f为C0~C8烷基。
步骤三、在步骤二制得的二-环氧烷酸烷基二酯中加入2~4倍摩尔量的不同分子量的聚乙二醇(PEG)和催化剂,80℃反应2~10 h,柱层析纯化除去未反应的PEG得后得产物,反应方程式如下,其中其中a为C2~C18烷基,b,c,d,f为C0~C8烷基;n为6~50的自然数。
所述步骤一中的酸性催化剂为对甲苯磺酸或硫酸,形态为固体或液体;步骤三所述的催化剂为三氟化硼乙醚。
所述的烷基二醇为1, 2-乙二醇、1, 4-丁二醇、1, 6-己二醇、1, 8-辛二醇、1,10-癸二醇、1, 12-十二烷二醇、1, 14-十四烷二醇、1, 16-十六烷二醇、1, 18-十八烷二醇。
所述的不饱和脂肪酸为棕榈油酸、油酸、亚油酸、亚麻酸。
所述的聚乙二醇为PEG300、PEG400、PEG600、PEG800、PEG1000、PEG1500、PEG2000。
所述步骤一中的不饱和脂肪酸、烷基二醇、酸性催化剂的摩尔比为(2~2.1)∶1∶(0.01~0.3),其反应温度为140~180℃,反应时间为2~10h。
所述步骤二中的二-不饱和脂肪酸烷基二醇二酯、间氯过氧苯甲酸的摩尔比为1∶(2~2.3),其反应温度为室温,反应时间为24~72h。
所述步骤三中的二-环氧烷酸烷基二醇二酯、聚乙二醇、催化剂的摩尔比为1∶(2~4)∶ (0.01~0.3),其反应温度为80℃,反应时间为2~10 h。
所述的不饱和脂肪酸优选油酸;烷基二醇优选1,12-十二烷基二醇;聚乙二醇优选PEG1000。
本发明的有益效果。
本发明聚氧乙烯基Gemini非表面活性剂结合了非离子表面活性剂的温和无刺激、易生物降解、环境友好的优点,还具备了Gemini表面活性剂的优异性能,如在保留增溶活性的同时,进一步提高了其作为注射剂增溶辅料的安全性,可广泛应用于医药工业中的液体制剂中使用,具有广阔的应用前景。
作为新型高安全性表面活性剂,聚氧乙烯基Gemini非表面活性剂还有许多突出特点:生物相容性良好,刺激性较小、不易溶血、安全使用浓度较Tween 80 提高了10倍,增溶作用较好;亲酯链由烷基二醇与不饱和脂肪酸酯化得到,即增长了碳链提高了增溶性能,在体内又可降解,提高了安全性。亲水端的聚氧乙烯链中具有多个乙氧基,与生物膜的亲和性低,生物相容性好,并且长度适中,易通过肾脏排泄。此外,整个反应过程不涉及有毒有害的过渡金属催化剂,无繁琐、复杂的保护脱保护过程,操作简单,适于工业化生产。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1。
一种聚氧乙烯基Gemini非离子表面活性剂,其结构式如下。
该聚氧乙烯基Gemini非离子表面活性剂的合成方法包括以下步骤。
步骤一、合成二-油酸十二烷基二醇二酯:1,12-十二烷二醇20.34 g(0.1 mol)和油酸56.49 g(0.2 mol)加入干燥的三颈烧瓶中,加入150 ml甲苯和0.768 g对甲苯磺酸。在三颈烧瓶口分别装上分水器和温度计,在氮气保护下进行反应。油浴加热至反应体系回流,回流反应3 h,停止反应。自然冷却至室温后,将烧瓶中的反应液倾倒入布氏漏斗中进行减压抽滤,滤液转移至梨形瓶中在旋转蒸发仪上减压除去甲苯得到粗产物74.01 g。IRKBr(cm-1): 2825.76, 2854.47, 1732.84, 1712.98, 1464.33, 1377.94, 1179.75, 722.56。1H-NMR (600 MHz, , ppm) δ: 5.36(m, 4H), 4.07(t, 4H), 2.31(t, 4H), 2.02(m, 8H),1.63(m, 8H), 1.45~1.28(m, 56H), 0.89(t, 6H)。13C-NMR (151 MHz, CDCl3, ppm) δ:173.99, 129.99, 129.75, 64.41, 34.41, 31.92, 29.78, 29.71, 29.57, 29.54,29.34, 29.28, 29.19, 29.15, 29.12, 28.67, 27.23, 27.18, 25.95, 25.03, 22.70,14.14。反应路线如下。
步骤二、合成二-8-环氧十八烷酸十二烷基二醇二酯:将步骤一合成得到的二-油酸十二烷基二醇酯74.01 g(0.1mol)溶于500 ml二氯甲烷中,分步添加2.2倍摩尔量的间氯过氧苯甲酸,室温搅拌反应72 h,过滤,滤液添加适量亚硫酸钠和碳酸氢钠还原中和未反应的间氯过氧苯甲酸,过滤,滤液经旋转蒸发仪减压除去二氯甲烷,得到粗品,上硅胶柱,用石油醚:乙酸乙酯=9:1洗脱后,得二-8-环氧十八烷酸十二烷基二醇酯纯品68.57g,产率89.85%。反应方程式如下,;IRKBr(cm-1): 2952.5, 2916.72, 2850.04, 1728.02, 1701.3,1575.13, 1464.79, 1418.65, 1377.29, 1259.25, 1214.10, 1185.29, 921.10,845.63, 748.56, 720.37, 668.03。1H-NMR (600 MHz, CDCl3, ppm) δ: 4.07(t, 4H),2.91(m, 4H), 2.31(t, 4H), 1.63(m, 8H), 1.51(m, 8H), 1.45~1.28(m, 56H), 0.89(t, 6H)。13C-NMR (151 MHz, CDCl3, ppm) δ: 173.99, 64.44, 57.28, 57.23, 50.84,34.36, 31.86, 29.56, 29.54, 29.36, 29.27, 29.23, 29.21, 29.06, 28.65, 27.83,27.80, 26.61, 26.57, 25.94, 24.96, 22.67, 14.11。反应路线式如下。
步骤三、合成二-9(8)PEG1000, 二-8(9)-羟基-十八烷酸十二烷基二醇二酯:在步骤二制得的二-8-环氧十八烷酸十二烷基二醇酯7.31 g(0.01mol)中加入4倍摩尔量的聚乙二醇1000(PEG1000)和催化剂1.5% 原料质量的三氟化硼乙醚,80℃反应5 h,上ODS柱层析,50%甲醇洗脱除去未反应的PEG1000,再甲醇洗脱后,得19.33g产物,产率70.60%。反应方程式如下,IRKBr(cm-1): 3343.65, 2928.77, 2862.31, 1736.08, 1643.8, 1457.19,1350.68, 1290.7, 1249.30, 1108.60, 951.34, 853.58。1H NMR (600 MHz, CDCl3, ppm)δ: 4.08 (t, 4H), 3.79(m, 6H), 3.63~3.69(m, 164H), 3.53(m, 2H), 3.11(m, 2H),2.31(t, 4H), 1.62(m, 8H), 1.28~1.37(m, 68H), 0.89(m, 6H)。13C NMR (151 MHz,CDCl3, ppm) δ: 174.03, 96.37, 84.49, 73.56, 72.49, 70.15~70.83(m), 64.43,63.00, 61.64, 50.78, 34.38, 33.02, 32.73, 31.88, 31.12, 29.13~29.92(m),28.63, 25.92, 25.75, 25.64, 25.59, 25.35, 25.02, 24.99, 22.67, 14.14。反应路线如下。
实施例2。
一种聚氧乙烯基Gemini非离子表面活性剂,其结构式如下。
该聚氧乙烯基Gemini非离子表面活性剂的合成方法包括以下步骤。
步骤一、步骤二同实施例1的步骤一和步骤二。
步骤三、合成二-9(8)PEG800, 二-8(9)-羟基-十八烷酸十二烷基二醇二酯:在步骤二制得的二-8-环氧十八烷酸十二烷基二醇酯7.31 g(0.01mol)中加入4倍摩尔量的聚乙二醇800(PEG800)和催化剂1.5% 原料质量的三氟化硼乙醚,80℃反应4 h,上ODS柱层析,50%甲醇洗脱除去未反应的PEG800,再甲醇洗脱后,得16.27g产物,产率63.52%。反应方程式如下,IRKBr(cm-1): 3459.68, 2930.39, 2860.5, 1737.06, 1646.28, 1457.29, 1350.96,1274.7, 1250.17, 1106.98, 1039.3, 950.71, 749.30。1H NMR (600 MHz, CDCl3, ppm)δ: 4.06 (t, 4H), 3.79(m, 8H), 3.63~3.69(m, 120H), 3.53(m, 1H), 3.11(m, 2H),2.30(t, 4H), 1.62(m, 8H), 1.28~1.37(m, 68H), 0.89(m, 6H)。13C NMR (151 MHz,CDCl3, ppm) δ: 174.03, 84.48, 73.57, 72.48, 70.15~70.83(m), 64.41, 63.00,61.64, 50.78, 34.38, 33.01, 32.73, 31.88, 31.12, 29.13~29.92(m), 28.63,25.92, 25.75, 25.64, 25.60, 25.34, 24.99, 22.68, 14.14。反应路线如下。
实施例3。
一种聚氧乙烯基Gemini非离子表面活性剂,其结构式如下。
该聚氧乙烯基Gemini非离子表面活性剂的合成方法包括以下步骤。
步骤一、步骤二同实施例1的步骤一和步骤二。
步骤三、合成二-9(8)PEG600, 二-8(9)-羟基-十八烷酸十二烷基二醇二酯:在步骤二制得的二-8-环氧十八烷酸十二烷基二醇酯7.31 g(0.01mol)中加入3倍摩尔量的聚乙二醇600(PEG600)和催化剂1.5% 原料质量的三氟化硼乙醚,80℃反应4 h,上ODS柱层析,50%甲醇洗脱除去未反应的PEG600,再甲醇洗脱后,得14.08g产物,产率72.39%。反应方程式如下,IRKBr(cm-1): 3309.9, 2928.86, 2859.12, 1736.29, 1654.5, 1457.23, 1350.70,1249.81, 1108.67, 950.78。1H NMR (600 MHz, CDCl3, ppm) δ: 4.06 (t, 4H), 3.79(m,8H), 3.63~3.69(m, 118H), 3.53(m, 1H), 3.11(m, 2H), 2.31(t, 4H), 1.62(m, 8H),1.28~1.37(m, 68H), 0.89(m, 6H)。13C NMR (151 MHz, CDCl3, ppm) δ: 174.03,84.44, 73.59, 72.45, 70.13~70.83(m), 64.43, 63.00, 61.63, 50.78, 34.38,33.00, 32.72, 31.88, 31.12, 29.13~29.92(m), 28.63, 25.92, 25.75, 25.64,25.60, 25.35, 25.34, 25.03, 24.99, 22.69, 22.68, 14.14。反应路线如下。
实施例4。
一种聚氧乙烯基Gemini非离子表面活性剂,其结构式如下。
该聚氧乙烯基Gemini非离子表面活性剂的合成方法包括以下步骤。
步骤一、步骤二同实施例1的步骤一和步骤二。
步骤三、合成二-9(8)PEG400, 二-8(9)-羟基-十八烷酸十二烷基二醇二酯:在步骤二制得的二-8-环氧十八烷酸十二烷基二醇酯中7.31 g(0.01mol)加入3倍摩尔量的聚乙二醇400(PEG400)和催化剂1.5% 原料质量的三氟化硼乙醚,80℃反应3 h,上ODS柱层析,50%甲醇洗脱除去未反应的PEG400,再甲醇洗脱后,得10.44g产物,产率65.58%。反应方程式如下,IRKBr(cm-1): 3288.5, 2930.25, 2860.5, 1736.65, 1657.2, 1457.80, 1350.78,1245.3, 1109.23, 951.03。1H NMR (600 MHz, CDCl3, ppm) δ: 4.08 (t, 4H), 3.79(m,6H), 3.63~3.69(m, 164H), 3.53(m, 2H), 3.11(m, 2H), 2.31(t, 4H), 1.62(m, 8H),1.28~1.37(m, 68H), 0.89(m, 6H)。13C NMR (151 MHz, CDCl3, ppm) δ: 174.03,96.37, 84.49, 73.56, 72.49, 70.15~70.83(m), 64.43, 63.00, 61.64, 50.78,34.38, 33.02, 32.73, 31.88, 31.12, 29.13~29.92(m), 28.63, 25.92, 25.75,25.64, 25.59, 25.35, 25.02, 24.99, 22.67, 14.14。反应路线如下。
实施例5。
一种聚氧乙烯基Gemini非离子表面活性剂,其结构式如下。
该聚氧乙烯基Gemini非离子表面活性剂的合成方法包括以下步骤。
步骤一、步骤二同实施例1的步骤一和步骤二。
步骤三、合成二-9(8)PEG300, 二-8(9)-羟基-十八烷酸十二烷基二醇二酯:在步骤二制得的二-8-环氧十八烷酸十二烷基二醇酯7.31 g(0.01mol)中加入3倍摩尔量的聚乙二醇300(PEG300)和催化剂1.5% 原料质量的三氟化硼乙醚,80℃反应2 h,上ODS柱层析,50%甲醇洗脱除去未反应的PEG300,再甲醇洗脱后,得8.89g产物,产率66.94%。反应方程式如下,IRKBr(cm-1): 3320.54, 2929.86, 2858.04, 1736.86, 1654.5, 1457.58, 1350.88,1248.69, 1108.07, 951.03, 739.71。1H NMR (600 MHz, CDCl3, ppm) δ: 4.08 (t, 4H),3.79(m, 6H), 3.63~3.69(m, 164H), 3.53(m, 2H), 3.11(m, 2H), 2.31(t, 4H), 1.62(m, 8H), 1.28~1.37(m, 68H), 0.89(m, 6H)。13C NMR (151 MHz, CDCl3, ppm) δ:174.03, 96.37, 84.49, 73.56, 72.49, 70.15~70.83(m), 64.43, 63.00, 61.64,50.78, 34.38, 33.02, 32.73, 31.88, 31.12, 29.13~29.92(m), 28.63, 25.92,25.75, 25.64, 25.59, 25.35, 25.02, 24.99, 22.67, 14.14。反应路线如下。
实施例6。
将制得的不同种类的聚氧乙烯基Gemini非离子表面活性剂采用HPLC/ELSD法进行纯度测试,色谱条件:Agilent 1200高效液相色谱仪,Alltech C18色谱柱(4.6×250mm,5μm),流动相为100% 甲醇,流速1mL/min。Grace Alltech ELSD 6000 蒸发光散射检测器,ELSD 漂移管温度60 ℃,氮气流速1.6 L/min。采用面积归一化法定量合成产物纯度(含量)。结果见下表。
实施例7。
将制得的不同种类的聚氧乙烯基Gemini非离子表面活性剂采用DataphysicsDCAT 21 表面张力仪吊片法对其进行表面活性测试,在20℃测定不同浓度的产品水溶液的表面张力(γ),通过γ-lgC的关系曲线,在拐点处对应的浓度即为临界胶束浓度CMC,并且使用最广泛的注射用增溶辅料Tween80进行对比,经测定临界胶束浓度(mol/L)及对应浓度的水溶液的表面张力(mN/m)见下表。
实施例8。
将制得的不同种类的聚氧乙烯基Gemini非离子表面活性剂,以紫杉醇为模型药,采用摇瓶法对其进行增溶性评价,在37℃测定不同浓度的产品水溶液中紫杉醇的饱和溶解度,采用最小二乘法对增溶剂浓度(X)-紫杉醇溶解度(Y)的关系进行线性回归,通过斜率评价不同产品的增溶能力,并且使用最广泛的注射用增溶辅料Tween80进行对比,结果见下表。
实施例9。
将制得的不同种类的聚氧乙烯基Gemini非离子表面活性剂,参照中华人民共和国药典2015年版四部 1148 溶血与凝聚检查法,采用兔红细胞对其进行安全性评价,配制不同浓度的表面活性剂的水溶液,在37℃观察其导致红细胞的溶血率,以5% 溶血率为限,确定增溶剂的安全使用浓度。并且使用最广泛的注射用增溶辅料Tween 80进行对比,结果见下表。并结合实施例8的数据,计算安全有效指数,综合考虑二-9(8)PEG1000, 二-8(9)-羟基-十八烷酸十二烷基二醇二酯为最佳的选择。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (11)
2.如权利要求1所述的一种聚氧乙烯基Gemini非离子表面活性剂,其特征在于,所述的a优选12,b、c、d、f优选7,所述的n优选20~24。
3.如权利要求1所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于,包括以下三个步骤:
步骤一、二-不饱和脂肪酸烷基二醇二酯的合成:在加装有分水器的三颈烧瓶加入不饱和脂肪酸、烷基二醇和酸性催化剂,以及带水剂,在氮气保护下,回流反应2~10h,冷却至室温后,减压抽滤,滤液在旋转蒸发仪上减压除去带水剂得到粗产物;
步骤二、将二-不饱和脂肪酸烷基二醇二酯溶于二氯甲烷中,分步添加2~2.3倍摩尔量的间氯过氧苯甲酸,室温搅拌24~72h,过滤,滤液添加适量亚硫酸钠和碳酸氢钠还原中和未反应的间氯过氧苯甲酸,过滤,滤液经旋转蒸发仪减压除去二氯甲烷,得到粗品,上硅胶柱,用石油醚-乙酸乙酯洗脱后得二-环氧烷酸烷基二醇二酯纯品;
步骤三、在步骤二制得的二-环氧烷酸烷基二醇二酯中加入2-4倍摩尔量的不同分子量的聚乙二醇(PEG)和催化剂,80℃反应5~10h,柱层析纯化除去未反应的PEG后得到产物。
4.如权利要求3所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于:步骤一中所述的酸性催化剂为对甲苯磺酸或硫酸,形态为固体或液体,带水剂为苯、甲苯或二甲苯;步骤三所述的催化剂为三氟化硼乙醚。
5.如权利要求3所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于,所述的烷基二醇为1,2-乙二醇、1,4-丁二醇、1,6-己二醇、1,8-辛二醇、1,10-癸二醇、1,12-十二烷二醇、1,14-十四烷二醇、1,16-十六烷二醇、1,18-十八烷二醇。
6.如权利要求3所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于,所述的不饱和脂肪酸为棕榈油酸、油酸。
7.如权利要求3所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于,所述的聚乙二醇为PEG 800、PEG 1000、PEG 1500、PEG 2000。
8.如权利要求3所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于:所述步骤一中的不饱和脂肪酸、烷基二醇、酸性催化剂的摩尔比为(2~2.1)∶1∶(0.01~0.3),其反应温度为140~180℃,反应时间为2~10h。
9.如权利要求3所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于:所述步骤二中的二-不饱和脂肪酸烷基二醇二酯、间氯过氧苯甲酸的摩尔比为1∶(2~2.3),其反应温度为室温,反应时间为24~72h。
10.如权利要求3所述的一种聚氧乙烯基Gemini非离子表面活性剂的合成方法,其特征在于:所述步骤三中的二-环氧烷酸烷基二醇二酯、聚乙二醇、催化剂的摩尔比为1∶(2~4)∶(0.01~0.3),其反应温度为80℃,反应时间为2~10h。
11.如权利要求1中所述的聚氧乙烯基Gemini非离子表面活性剂作为药用辅料在制备药物中应用。
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