CN114209655B - 度鲁特韦微粉制备方法 - Google Patents
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- 229960002542 dolutegravir Drugs 0.000 title claims abstract description 79
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 85
- 230000000694 effects Effects 0.000 claims abstract description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 12
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 5
- 235000019832 sodium triphosphate Nutrition 0.000 claims description 5
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- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 3
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 3
- 239000000243 solution Substances 0.000 abstract description 22
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- 239000012267 brine Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
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- 238000011161 development Methods 0.000 description 2
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- 238000005516 engineering process Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940014075 tivicay Drugs 0.000 description 2
- VERWQPYQDXWOGT-LVJNJWHOSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VERWQPYQDXWOGT-LVJNJWHOSA-N 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VJWIXTLPDOVKPN-UHFFFAOYSA-N Gelsemine Natural products CN1CC2(C=C)C3CC4OC3C1C2CC45C(=O)Nc6ccccc56 VJWIXTLPDOVKPN-UHFFFAOYSA-N 0.000 description 1
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- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
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- NFYYATWFXNPTRM-QJICHLCESA-N gelsemine Chemical compound OC1=NC2=CC=CC=C2[C@@]21[C@H]1[C@H]3[C@H]4CO[C@@H]2C[C@H]4[C@]1(C=C)CN3C NFYYATWFXNPTRM-QJICHLCESA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了度鲁特韦微粉制备方法,包括在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为50mg/ml‑100mg/ml,在另一反应釜内,采用纯净水配制含盐水溶液,其中盐浓度为1%‑5%,将上述含盐水溶液开启强力搅拌混合等步骤,本发明采用含盐水溶液,特别是三聚磷酸钠、乙二胺四乙酸二钠或乙二胺二琥珀酸三钠的水溶液,具有特别优良的超微效果。一方面这类物质的加入能大幅度降低析出晶体的温度,第二方面,这类水溶液具有表面张力低和优良的分散稳定效果,特别有利于从乙醇这种易溶溶剂中析出超细纳米晶体,并不易聚并。
Description
技术领域
本发明属于有机化学技术领域,具体地说,涉及度鲁特韦微粉制备方法。
背景技术
度鲁特韦(德罗格韦,Dolutegravir,Tivicay)是由英国制药巨头葛兰素史克(GSK)与日本盐野义制药公司(Shionogi)合作开发的一种抗艾滋病新药。 2012年7月葛兰素史克制药公司和日本盐野义制药公司公布了艾滋病新药 Dolutegravir的三期临床试验结果,在接受dolutegravir药物以及其他两种老版艾滋病药物治疗48周之后,患者体内88%的病毒被成功抑制,而服用吉利德科学公司(GileadSciences)的三合一的口服药品Atripla(依法韦恩茨/恩曲他滨/ 替诺福韦富马酸片)之后,患者体内81%的病毒被抑制,由此可以看出,葛兰素史克制药公司的dolutegravir药物略胜一筹。据研究人员表示,在比对试验中,由于药物的副作用,10%的患者最终停止服用了吉利德科技技术公司的Atripla药物,但是仅有2%的患者停止服用葛兰素史克制药公司的dolutegravir药物,由此可见葛兰素史克dolutegravir药物的安全性略高。
美国FDA以优先审评肯定了该药的突破性,于2013年8月12日批准其上市。临床使用度鲁特韦钠盐(dolutegravir sodium,商品名为Tivicay,DTGS),结构式见下,剂型为10、25及50mg薄膜包衣片,目前国内尚未批准该药物的进口。
度鲁特韦虽然性能优良,但其在水中的溶解性太差,从而影响其生物利用度。当以悬浮液形式给药时,严重受限于其溶出度或溶解度。度鲁特韦钠几乎不溶于缓冲液,属于低溶解度药物,不可申请生物等效性试验豁免。
药物的微粉形态可以极大提高药物的生物利用度。度鲁特韦产品易于结晶,得到的微粉一般粒径都大于20微米以上。因此目前开发合适的度鲁特韦微粉制备方法将极大推动相关行业的发展。
发明内容
针对现有技术中存在的问题,本发明提供了一种度鲁特韦微粉制备方法,是通过以下技术方案来实现的:
一种度鲁特韦微粉制备方法,包括以下步骤:
1)在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为50mg/ml-100mg/ml;
2)在另一反应釜内,采用纯净水配制含盐水溶液,其中盐浓度为1%-5%;
3)将上述含盐水溶液开启强力搅拌,控制在温度-10-10℃的条件下,通过高压输送泵将度鲁特韦的乙醇溶液,通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,继续强力搅拌30min-60min,得到度鲁特韦混悬液;
4)将该混悬液进行固液分离,干燥后即可得到度鲁特韦微粉产品。
作为进一步地改进,本发明所述的步骤1)中的度鲁特韦的浓度为 50mg/ml-100mg/ml。
作为进一步地改进,本发明所述的步骤2)中盐水溶液的盐浓度为1%-5%。
作为进一步地改进,本发明所述的盐为三聚磷酸钠、乙二胺四乙酸二钠或乙二胺二琥珀酸三钠中的任意一种。
作为进一步地改进,本发明所述的含盐水溶液与度鲁特韦的乙醇溶液的体积比为5-50:1。
作为进一步地改进,本发明所述的度鲁特韦的乙醇溶液是通过高压输送泵将度鲁特韦的乙醇溶液进一步通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,且反应器的喷射混合器浸入反应釜的液相中。
作为进一步地改进,本发明所制备而成的度鲁特韦微粉,粒径D90小于1.0 微米,优选为0.1-0.5微米。
本发明采用了反溶剂法重结晶得到度鲁特韦微粉的工艺,具有如下技术效果:
(1)采用含盐水溶液,特别是三聚磷酸钠、乙二胺四乙酸二钠或乙二胺二琥珀酸三钠的水溶液,具有特别优良的超微效果。一方面这类物质的加入能大幅度降低析出晶体的温度,第二方面,这类水溶液具有表面张力低和优良的分散稳定效果,特别有利于从乙醇这种易溶溶剂中析出超细纳米晶体,并不易聚并。
(2)度鲁特韦的乙醇溶液是通过高压输送泵将度鲁特韦的乙醇溶液进一步通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,且所述的反应器的喷射混合器浸入反应釜的液相中。一般常规反溶剂重结晶工艺中都是慢慢滴加溶液,发现效果不好。而采用本发明工艺,不仅可以有效控制流体流动处于完全发展的高速湍流状态,有利于实现超微效果;而且由于喷射混合器会大量带入气体,形成气液充分混合,对液滴的破碎效果极其明显,并且会形成空泡效应,特别有利于形成超细纳米晶体。
(3)这种新型工艺的应用是本发明得以实现度鲁特韦微粉制备的核心和关键技术,所制备了度鲁特韦微粉,粒径D90小于1.0微米,优选为0.1-0.5微米,都远高于传统工艺和文献报道。
附图说明
图1为设置在反应釜上的基于文丘里效应的喷射混合器示意图。
具体实施方式
下面通过具体实施例对本发明的技术方案作进一步地说明:
实施例1
(1)在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为50mg/ml。
(2)在另一反应釜内,采用纯净水配制三聚磷酸钠水溶液,浓度为1%。
(3)将上述含盐水溶液开启强力搅拌,控制在温度-10℃的条件下,通过高压输送泵将度鲁特韦的乙醇溶液,通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,且反应器的喷射混合器浸入反应釜的液相中。继续强力搅拌60min。得到度鲁特韦混悬液。其中含盐水溶液与度鲁特韦的乙醇溶液的体积比为5:1,图1为设置在反应釜上的基于文丘里效应的喷射混合器示意图。
(4)将该混悬液进行固液分离,干燥后即可得到度鲁特韦微粉产品。所得度鲁特韦微粉,粒径D90为0.50微米。
实施例2
(1)在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为100mg/ml。
(2)在另一反应釜内,采用纯净水配制乙二胺四乙酸二钠水溶液,浓度为5%。
(3)将上述含盐水溶液开启强力搅拌,控制在温度10℃的条件下,通过高压输送泵将度鲁特韦的乙醇溶液,通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,且反应器的喷射混合器浸入反应釜的液相中。继续强力搅拌30min。得到度鲁特韦混悬液。其中含盐水溶液与度鲁特韦的乙醇溶液的体积比为50:1,图1为设置在反应釜上的基于文丘里效应的喷射混合器示意图。
(4)将该混悬液进行固液分离,干燥后即可得到度鲁特韦微粉产品。所得度鲁特韦微粉,粒径D90为0.20微米。
实施例3
(1)在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为75mg/ml。
(2)在另一反应釜内,采用纯净水配制乙二胺二琥珀酸三钠水溶液,浓度为 3%。
(3)将上述含盐水溶液开启强力搅拌,控制在温度0℃的条件下,通过高压输送泵将度鲁特韦的乙醇溶液,通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,且反应器的喷射混合器浸入反应釜的液相中。继续强力搅拌45min。得到度鲁特韦混悬液。其中含盐水溶液与度鲁特韦的乙醇溶液的体积比为25:1,图1为设置在反应釜上的基于文丘里效应的喷射混合器示意图。
(4)将该混悬液进行固液分离,干燥后即可得到度鲁特韦微粉产品。所得度鲁特韦微粉,粒径D90为0.10微米。
对照例1
(1)在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为75mg/ml。
(2)在另一反应釜内,放入纯净水。
(3)开启强力搅拌,控制在温度0℃的条件下,通过高压输送泵将度鲁特韦的乙醇溶液,通过设置在反应釜上的基于文丘里效应的喷射混合器喷入水中,且反应器的喷射混合器浸入反应釜的液相中。继续强力搅拌45min。得到度鲁特韦混悬液。其中纯净水与度鲁特韦的乙醇溶液的体积比为25:1。
(4)将该混悬液进行固液分离,干燥后即可得到度鲁特韦微粉产品。所得度鲁特韦微粉,粒径D90为5.0微米。
可见,对照例1和实施例3相对比,由于没能采用三聚磷酸钠、乙二胺四乙酸二钠或乙二胺二琥珀酸三钠的水溶液作为反溶剂,所得度鲁特韦微粉的粒径D90 显著上升,达到了5.0微米。
对照例2
(1)在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为75mg/ml。
(2)在另一反应釜内,放入纯净水。
(3)开启强力搅拌,控制在温度0℃的条件下,将度鲁特韦的乙醇溶液滴加到纯净水中,继续强力搅拌45min。得到度鲁特韦混悬液。其中纯净水与度鲁特韦的乙醇溶液的体积比为25:1。
(4)将该混悬液进行固液分离,干燥后即可得到度鲁特韦微粉产品。所得度鲁特韦微粉,粒径D90为28.0微米。
可见,对照例1和对照例2相对比,由于没能采用基于文丘里效应的喷射混合器喷入水中,采用了传统的滴加方式,所得度鲁特韦微粉的粒径D90显著上升,达到了28.0微米。
最后,还需要注意的是,以上列举的仅是本发明的具体实施例子。显然,本发明不限于以上实施例子,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (1)
1.度鲁特韦微粉制备方法,其特征在于,包括以下步骤:
1)在反应釜内,加入溶剂乙醇,将度鲁特韦原粉溶于乙醇中,配制成度鲁特韦的乙醇溶液,其中度鲁特韦的浓度为50mg/ml-100mg/ml;
2)在另一反应釜内,采用纯净水配制含盐水溶液,其中盐浓度为1%-5%;
3)将上述含盐水溶液开启强力搅拌,控制在温度-10-10℃的条件下,通过高压输送泵将度鲁特韦的乙醇溶液,通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,继续强力搅拌30min-60min,得到度鲁特韦混悬液;
4)将该混悬液进行固液分离,干燥后即可得到度鲁特韦微粉产品;
所述的步骤1)中的度鲁特韦的浓度为50mg/ml-100mg/ml;所述的步骤2)中盐水溶液的盐浓度为1%-5%,所述的含盐水溶液与度鲁特韦的乙醇溶液的体积比为5-50:1;
所述的盐为三聚磷酸钠、乙二胺四乙酸二钠或乙二胺二琥珀酸三钠中的任意一种;
所述的度鲁特韦的乙醇溶液是通过高压输送泵将度鲁特韦的乙醇溶液进一步通过设置在反应釜上的基于文丘里效应的喷射混合器喷入含盐水溶液中,且所述的反应器的喷射混合器浸入反应釜的液相中;
所制备而成的度鲁特韦微粉,粒径D90为0.1-0.5微米。
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