CN114957591A - 一种用于药物缓释的cof基聚氨酯多孔膜的制备方法 - Google Patents
一种用于药物缓释的cof基聚氨酯多孔膜的制备方法 Download PDFInfo
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- CN114957591A CN114957591A CN202210297841.8A CN202210297841A CN114957591A CN 114957591 A CN114957591 A CN 114957591A CN 202210297841 A CN202210297841 A CN 202210297841A CN 114957591 A CN114957591 A CN 114957591A
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- cof
- porous membrane
- based polyurethane
- aldehyde
- drug
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Abstract
本发明提供一种用于药物缓释的COF基聚氨酯多孔膜的制备方法，包括以下步骤：（1）制备羟基修饰的COF多孔材料，将其加入二异氰酸酯中分散均匀，之后加入多元醇和催化剂反应；（2）加入扩链剂至NCO反应完全，将反应液缓慢倒入模具中，室温固化成型，即得到COF基聚氨酯多孔膜。将多孔膜浸泡在装有药物溶液的玻璃瓶中，一定时间后取出烘干，即制得负载药物的COF基聚氨酯多孔膜。本发明制备工艺简单，无需使用表面活性剂，制备的多孔材料具有优异的柔顺性、生物相容性和可加工性能，解决了当前聚氨酯药物缓释材料力学强度低、释放速度难以控制、载药量较低的问题。
Description
技术领域
本发明涉及属于生物化学技术领域，具体涉及一种可用于药物缓释的新型COF基聚氨酯多孔膜材料的制备方法。
背景技术
在传统的医药领域中，口服药因疗效好、使用方便等特点占据了极大的市场，然而，药物分子进入人体后因代谢加快，需要频繁服用，导致其在人体内有较高的残留浓度，对人体产生不可避免的毒副作用。为了解决口服类药物半衰期短，服用频繁，副作用大和生物利用度低的问题，对药物缓释的研究是非常必要的。有效的药物缓释系统需要能够吸附、储存和释放药物分子的能力。相比起通过化学键将药物结合到载体上，通过非化学作用的方式吸附到材料内部显然更加直接，操作也更加简单安全。
目前药物缓释类材料主要包括具有生物相容性的大分子或聚合物等有机材料、介孔硅酸盐材料等无机材料两大类。但两类材料都各有利弊，有机材料可以较好地包覆药物分子，但其材料孔隙率波动较大，导致其药物释放速度难以控制。而无机材料虽具有较好的孔道分布和比表面积，但其力学性能较差，限制了其进一步的发展。如何将有机材料与无机材料的优点结合起来，成为近年来的研究重点。CN103191470B制备了一种有机/无机复合多孔材料，选取生物可降解性的脂溶性有机聚合物材料、磷酸钙类生物材料等无机材料，将其分散于溶剂中后加入药物，分散均匀后除去溶剂即制得有机/无机复合材料。该方法较为有效的结合了有机材料和无机材料的优势，但其制品主要为物理混合，力学性能相对较差。聚合物降解后产物多为酸性物质，不利于人体细胞成长。CN107349111A公开了一种多孔框架材料在面膜中的应用，其将多孔框架材料作为基质应用于功能面膜，多孔框架材料(MOFs或COFs)作为无菌防腐剂或能够缓释活性成分的载体负载活性成分，改善了现有材料对皮肤有较大刺激性、负载活性物质较低、皮肤难以吸收等缺点，但多孔材料需依赖甘油、水等液体才能较好地分散在面膜材料中，且受本身结构影响，耐酸碱性能较差。US2017247493A1提供了一种化学性能稳定的中空球形共价有机骨架(COF)的制备方法，其具有高表面积的中孔壁，但其制备过程复杂，需在严格隔绝空气在玻璃管中进行。
聚氨酯材料具有良好的生物相容性，对生物体无毒无害，且其制品具有优异的耐磨性、韧性，易成型加工，性能可设计，被广泛应用于人造血管、人造骨骼等生物材料领域。目前，聚氨酯材料在药物缓释领域主要有两种途径的应用，一为通过界面聚合等方式，在表面活性剂的作用下，将油溶性的异氰酸酯与水溶性的多羟基化合物反应，经扩链后制备得到聚氨酯微胶囊，该方法操作简单，适用于液体材料的包封，聚氨酯微胶囊具有良好的致密性，但其制备过程中需使用较多的乳化剂，可能导致细胞损伤，限制了其在生物领域的应用；二为由软段和硬段相互交联制备得到的聚氨酯水凝胶，水凝胶具有优异的生物相容性，在生物体中可保持稳定的性能，但其强度较低，且对环境条件敏感，载药量较低，药物缓释速度较难控制。专利CN113058514A制备了一种耐高温的聚氨酯微胶囊材料，其制备的材料具有高温缓释的效果，其微孔结构主要由扩链剂提供，药物释放能力有限，仅适用于包覆有较强挥发性的分子，且需高温条件进行释放。专利CN104804167B制备了一种双重响应型的聚氨酯水凝胶，所制备的材料具有光和还原剂双重响应性，但其材料药物吸附性能主要由交联剂提供的网状结构提供，药物负载、缓释能力不易控制。
发明内容
针对现有技术的不足，本发明提供一种用于药物缓释的COF基聚氨酯多孔膜的制备方法。避免使用有细胞毒性的表面活性剂，制备的COF基聚氨酯基多孔膜材料可有效提升载药量并控制缓释速度、力学性能优异，且有较好的耐酸碱性、多孔性、生物相容性、高强度和优异的可加工性能等优点。
为解决以上技术问题，本发明提供以下技术方案：
一种用于药物缓释的COF基聚氨酯多孔膜的制备方法，包括以下步骤：
(1)取0.5～2质量份COF多孔材料加入到3～7质量份二异氰酸酯中，加入0.005～0.02质量份催化剂，50～90℃高速分散反应一段时间，之后加入15～30质量份多元醇、0.005～0.02质量份催化剂搅拌均匀，在60～90℃下继续反应；
(2)待混合体系NCO含量稳定后，向其中加入0.3～1质量份扩链剂，混合均匀，在60～90℃下继续反应，待NCO反应完毕后将反应液缓慢倒入模具中，室温放置固化成型，即得到COF基聚氨酯多孔膜。
本发明优选的，所述步骤(1)中，所述的二异氰酸酯为异佛尔酮二异氰酸酯(IPDI)、4,4'-二环己基甲烷二异氰酸酯(HMDI)、六亚甲基二异氰酸酯(HDI)中的一种或多种混合物。
本发明优选的，步骤(1)中，所述的COF多孔材料为孔道内壁中含有羟基修饰的COF粉末材料。
本发明优选的，步骤(1)中，高速分散速度为1000r/min～3000r/min，分散时间为0.5～2h。
本发明优选的，步骤(1)中，多元醇为聚乙二醇、聚丙二醇、聚四氢呋喃醚二醇、聚氧四亚甲基二醇、四氢呋喃与环氧乙烷的共聚二醇、聚(氧基-1，2-丙烯)二醇、蓖麻油多元醇中的一种或多种，更优选为聚丙二醇(PPG)和/或聚四氢呋喃醚二醇(PTMEG)。
本发明优选的，步骤(1)中，催化剂为有机锡、有机铋、叔胺类催化剂中的一种或多种，更优选为叔胺类催化剂。
本发明优选的，步骤(2)中，扩链剂为1，4-丁二醇、2，3-丁二醇、二甘醇、三羟甲基丙烷、山梨醇、2，2-二羟甲基丙酸、N-甲基二乙醇胺中的一种或多种，更优选的为2，2-二羟甲基丙酸。
本发明优选的，所述的COF多孔材料的制备方法，包括以下步骤：将氨基芳香化合物、醛基羟基芳香化合物、催化剂、有机溶剂加热反应，抽滤，洗涤，干燥后即得到COF多孔材料。
本发明优选的，所述的氨基芳香化合物中，氨基取代基的个数至少为二取代，芳香单元的种类包括但不限于苯基、联苯基、1,3,5-三苯基苯、1,3,5-三苯基-2,4,6-三嗪、1,2,3,4,5,6-六苯基取代苯、1,3,5-三(4-氨基苯基)苯、芴、螺二芴、芴酮、芘、三苯胺、噻吩、咔唑、苯并咪唑或四苯基乙烯，更优选的为1,3,5-三(4-氨基苯基)苯。
本发明优选的，所述的醛基羟基芳香化合物中，醛基取代基的个数至少为二取代，羟基取代基的个数为1-4，作为醛基羟基芳香化合物的骨架，芳香单元的种类包括但不限于苯基、联苯基、1,3,5-三苯基苯、1,3,5-三苯基-2,4,6-三嗪、1,2,3,4,5,6-六苯基取代苯、芴、螺二芴、芴酮、芘、三苯胺、噻吩、咔唑、苯并咪唑或四苯基乙烯。
本发明优选的，所述的醛基羟基芳香化合物中，醛基和羟基的基团数量比为1:1～1:0。
优选的，所述醛基羟基芳香化合物为2，5-二羟基-1，4-对苯二甲醛。
本发明所述的COF多孔材料的制备方法中，优选的，所述的催化剂为醋酸溶液，优选的催化剂浓度为3～15wt％。
本发明所述的COF多孔材料的制备方法中，优选的，所述的有机溶剂为1,4-二氧六环、均三甲苯、正丁醇、邻二氯苯、N,N-二甲基甲酰胺、二甲基亚砜、甲醇、甲苯、四氢呋喃中的一种或多种。
本发明所述的COF多孔材料的制备方法中，优选的，所述的反应温度为80～180℃，更优选的反应温度为100～120℃。
本发明所述的COF多孔材料的制备方法中，优选的，所述的反应时间为24～72h，更优选的反应时间为48～72h。
本发明的COF基聚氨酯多孔膜材料的比表面积为200～4000m2/g。由于COF材料的加工性能差，本发明利用COF孔道内的-OH与异氰酸酯的NCO基团反应，将具有多孔性能的COF材料引入至聚氨酯材料中。由于聚氨酯良好的生物相容性、柔韧性和易成型加工等性能，使得所制备的多孔膜兼具柔顺性、多孔性、生物相容性和可加工性能。
本发明还提供一种负载药物的COF基聚氨酯多孔膜的制备方法，包括以下步骤：将COF基聚氨酯多孔膜浸泡在药物溶液中，在一定温度下，浸泡一段时间，烘干，即制得负载药物的COF基聚氨酯多孔膜。
本发明所述的负载药物的COF基聚氨酯多孔膜的制备方法中，优选的，浸泡温度为30～40℃，更优选为33～38℃。
本发明所述的负载药物的COF基聚氨酯多孔膜的制备方法中，优选的，浸泡时间为24～72h。更优选为35～50h。
本发明具有以下有益效果：
(1)制备过程简单，无需使用对生物细胞有害的溶剂、表面活性剂；
(2)将COF粉末材料加工成COF膜，实现了COF材料的可加工性能，克服了COF材料耐酸碱性能较差的特点，提升了COF基的应用性能；
(3)将聚氨酯的优势与COF材料的优势整合起来，将有多孔性能的COF材料引入至聚氨酯材料中，制备出的COF基聚氨酯膜材料拉伸强度可达20-30MPa，断裂伸长率可达350-500％，表现出良好的力学性能；且有较好的耐酸碱性、多孔性、生物相容性、高强度和优异的可加工性能。
(4)得益于COF的多孔性和聚氨酯的生物相容性，通过调整COF的比例，该COF多孔聚氨酯膜材料可有效提升载药量，并实现对药物缓释速度的控制，使其在生物医药方面发挥重要作用。该材料尤其适用于医用绷带、创口敷料、胶囊等医药领域。本发明制备的膜材料还可根据实际应用需求，加工成胶囊等，用于粉末药物在组织液中的释放。
附图说明
图1为COF-1氮气吸附脱附曲线；
图2为COF-2氮气吸附脱附曲线；
图3为COF-1基聚氨酯多孔膜吸附脱附曲线；
图4为COF-2基聚氨酯多孔膜吸附脱附曲线；
图5为COF-1核磁谱图；
图6为COF-1扫描电镜图。
具体实施方式
下列实施实例用以更详细地描述本发明方案，但本发明并不局限于实施例所描述的方案。
药物缓释速率的检测方法：
(1)配制氯霉素标准水溶液(50μg/ml)，用紫外分光光度计确定最大吸收波长；
(2)配制不同浓度梯度(20μg/ml、50μg/ml、100μg/ml、200μg/ml、500μg/ml)的氯霉素水溶液，用紫外分光光度计在最大吸收波长处测定不同浓度溶液的吸光度，作图得到浓度与吸光度的标准工作曲线。
(3)将1～2g负载药物的COF基聚氨酯多孔膜浸泡于500ml去离子水中，氯霉素随即缓释出来，测试不同时间氯霉素水溶液的吸光度，可以计算出不同时间氯霉素浓度，进而得知缓释速度。
COF-1的制备
(1)将7.02g M1与4.98g M2加入到100mL三口瓶中，加入1，4-二氧六环为溶剂，升温至120℃，磁力搅拌下反应72h；
(2)反应结束后，抽滤，用四氢呋喃、甲醇和丙酮分别洗涤，并用四氢呋喃和甲醇分别索式提取24h，60℃下真空干燥24h，得到粉末状COF-1多孔材料；
(3)以氮气为吸附质进行COF-1的气体吸附/脱附测试，制备的COF-1材料具有明显的多孔性能，比表面积为548m2/g。
COF-2的制备
(1)将7.08g M3与4.98g M2加入到100mL三口瓶中，加入1，4-二氧六环为溶剂，升温至120℃，磁力搅拌下反应72h；
(2)反应结束后，抽滤，用四氢呋喃、甲醇和丙酮分别洗涤，并用四氢呋喃和甲醇分别索式提取24h，60℃下真空干燥24h，得到粉末状COF-2多孔材料；
(3)以氮气为吸附质进行COF-2的气体吸附/脱附测试，制备的COF-2材料具有明显的多孔性能，比表面积为519m2/g。
实施例1
(1)取7g异佛尔酮二异氰酸酯，加入1g粉末状COF-1多孔材料及0.02g三亚乙基二胺，90℃条件下以1000r/min分散2h，之后向混合体系中加入20g聚丙二醇2000及0.01g三亚乙基二胺，混合均匀，在85℃下继续反应。当混合溶液NCO含量稳定后，加入0.5g 2，2-二羟甲基丙酸，继续反应至NCO完全消耗。将反应液缓慢倒入模具中，室温放置固化成型，即得到COF基聚氨酯多孔膜。测试聚氨酯多孔膜的氮气吸附脱附曲线，所制备的聚氨酯多孔膜的比表面积为369m2/g。
(2)取5g成型的COF基聚氨酯多孔膜，将其浸泡在装有3mg/ml的氯霉素水溶液的玻璃瓶中，放置在37℃下，48h后将聚氨酯多孔膜取出烘干，即制得负载药物的聚氨酯多孔膜。
(3)将1g负载药物的COF基聚氨酯多孔膜浸泡于500ml去离子水中，通过荧光分光光度计测试药物的荧光光谱，测试不同时间去离子水溶液中药物的荧光强度，计算出多孔膜的药物负载量为COF基聚氨酯多孔膜质量的26％，72h药物可释放90％。
(4)使用美特斯CMT4202万能试验机测试COF基聚氨酯多孔膜的力学性能(测试标准为GB/T 528-2009)，断裂强度为25MPa，断裂伸长率为480％，浸泡于10％NaOH溶液48h无异常，10％H2SO4溶液48h无异常。
实施例2
(1)取5g异佛尔酮二异氰酸酯，加入1.5g粉末状COF-1多孔材料及0.02g三亚乙基二胺，80℃条件下以3000r/min分散2h，之后向混合体系中加入15g聚丙二醇2000及0.01g三亚乙基二胺，混合均匀，在80℃下继续反应。当混合溶液NCO含量稳定后，加入0.3g 2，2-二羟甲基丙酸，继续反应至NCO完全消耗。将反应液缓慢倒入模具中，室温放置固化成型，即得到COF基聚氨酯多孔膜。
(2)取5g成型的COF基聚氨酯多孔膜，将其浸泡在装有3mg/ml的氯霉素水溶液的玻璃瓶中，放置在37℃下，48h后将聚氨酯多孔膜取出烘干，即制得负载药物的聚氨酯多孔膜。
(3)将1g负载药物的COF基聚氨酯多孔膜浸泡于500ml去离子水中，通过荧光分光光度计测试药物的荧光光谱，测试不同时间去离子水溶液中药物的荧光强度，计算出多孔膜的药物负载量为COF基聚氨酯多孔膜质量的38％，48h药物可释放93％。
(4)使用美特斯CMT4202万能试验机测试COF基聚氨酯多孔膜的力学性能(测试标准为GB/T 528-2009)，断裂强度为23MPa，断裂伸长率为420％，浸泡于10％NaOH溶液48h无异常，10％H2SO4溶液48h无异常。
实施例3
(1)取6g 4,4'-二环己基甲烷二异氰酸酯，加入1.5g粉末状COF-1多孔材料及0.02g三亚乙基二胺，80℃条件下以3000r/min分散2h，之后向混合体系中加入15g聚丙二醇2000及0.01g三亚乙基二胺，混合均匀，在80℃下继续反应。当混合溶液NCO含量稳定后，加入0.3g 2，2-二羟甲基丙酸，继续反应至NCO完全消耗。将反应液缓慢倒入模具中，室温放置固化成型，即得到COF基聚氨酯多孔膜。
(2)取5g成型的COF基聚氨酯多孔膜，将其浸泡在装有3mg/ml的氯霉素水溶液的玻璃瓶中，放置在37℃下，48h后将聚氨酯多孔膜取出烘干，即制得负载药物的聚氨酯多孔膜。
(3)将1g负载药物的COF基聚氨酯多孔膜浸泡于500ml去离子水中，通过荧光分光光度计测试药物的荧光光谱，测试不同时间去离子水溶液中药物的荧光强度，计算出多孔膜的药物负载量为COF基聚氨酯多孔膜质量的33％，48h药物可释放90％。
(4)使用美特斯CMT4202万能试验机测试COF基聚氨酯多孔膜的力学性能(测试标准为GB/T 528-2009)，断裂强度为23MPa，断裂伸长率为380％，浸泡于10％NaOH溶液48h无异常，10％H2SO4溶液48h无异常。
实施例4
(1)取7g异佛尔酮二异氰酸酯，加入1g粉末状COF-2多孔材料及0.02g三亚乙基二胺，90℃条件下以1000r/min分散2h，之后向混合体系中加入20g聚丙二醇2000及0.01g三亚乙基二胺，混合均匀，在85℃下继续反应。当混合溶液NCO含量稳定后，加入0.5g 2，2-二羟甲基丙酸，继续反应至NCO完全消耗。将反应液缓慢倒入模具中，室温放置固化成型，即得到COF基聚氨酯多孔膜。测试聚氨酯多孔膜的氮气吸附脱附曲线，所制备的聚氨酯多孔膜的比表面积为260m2/g。
(2)取5g成型的COF基聚氨酯多孔膜，将其浸泡在装有3mg/ml的氯霉素水溶液的玻璃瓶中，放置在37℃下，48h后将聚氨酯多孔膜取出烘干，即制得负载药物的聚氨酯多孔膜。
(3)将1g负载药物的COF基聚氨酯多孔膜浸泡于500ml去离子水中，通过荧光分光光度计测试药物的荧光光谱，测试不同时间去离子水溶液中药物的荧光强度，计算出多孔膜的药物负载量为COF基聚氨酯多孔膜质量的24％，72h药物可释放85％。
(4)使用美特斯CMT4202万能试验机测试COF基聚氨酯多孔膜的力学性能(测试标准为GB/T 528-2009)，断裂强度为24MPa，断裂伸长率为410％，浸泡于10％NaOH溶液48h无异常，10％H2SO4溶液48h无异常。
对比例1
(1)取7g异佛尔酮二异氰酸酯，加入20g聚丙二醇2000及0.02g三亚乙基二胺，混合均匀，在85℃下反应。当混合溶液NCO含量测试值稳定后，加入0.5g 2，2-二羟甲基丙酸，继续反应至NCO完全消耗。将反应液缓慢倒入模具中，室温放置固化成型，即得到聚氨酯膜。
(2)取5g成型的聚氨酯膜，将其浸泡在装有3mg/ml的氯霉素水溶液的玻璃瓶中，放置在37℃下，48h后将聚氨酯多孔膜取出烘干，即制得负载药物的聚氨酯多孔膜。
(3)将负载药物聚氨酯膜浸泡于去离子水中，通过荧光分光光度计测试药物的荧光光谱，测试不同时间去离子水溶液中药物的荧光强度，计算出多孔膜的药物负载量为COF基聚氨酯多孔膜质量的4.5％，72h药物可释放70％。
(4)使用美特斯CMT4202万能试验机测试COF基聚氨酯多孔膜的力学性能(测试标准为GB/T 528-2009)，断裂强度为25MPa，断裂伸长率为460％，浸泡于10％NaOH溶液48h无异常，10％H2SO4溶液48h无异常。
对比例2
(1)取5gCOF-1粉末，将其浸泡在装有3mg/ml的氯霉素水溶液的玻璃瓶中，放置在37℃下，48h后取出烘干。
(2)将1g负载药物的COF粉末浸泡于去离子水中，通过荧光分光光度计测试药物的荧光光谱，测试不同时间去离子水溶液中药物的荧光强度，计算出COF的药物负载量为其质量的20％，72h药物可释放90％。
Claims (10)
1.一种用于药物缓释的COF基聚氨酯多孔膜的制备方法，包括以下步骤：
（1）取0.5~2 质量份COF多孔材料加入到3~7质量份二异氰酸酯中，加入0.005~0.02 质量份催化剂，50~90℃高速分散反应一段时间，之后加入15~30 质量份多元醇、0.005~0.02质量份催化剂搅拌均匀，在60~90℃下继续反应；
（2）待混合体系NCO含量稳定后，向其中加入0.3~1 质量份扩链剂，混合均匀，在60~90℃下继续反应，待NCO反应完毕后将反应液缓慢倒入模具中，室温放置固化成型，即得到COF基聚氨酯多孔膜。
2.根据权利要求1所述的方法，其特征在于，所述步骤（1）中二异氰酸酯为异佛尔酮二异氰酸酯、4,4'-二环己基甲烷二异氰酸酯、六亚甲基二异氰酸酯中的一种或多种。
3.根据权利要求1或2所述的方法，其特征在于，所述步骤（1）中COF材料为孔道内壁中含有羟基修饰的COF粉末材料。
4.根据权利要求1-3任一项所述的方法，其特征在于，所述步骤（1）中，多元醇为聚乙二醇、聚丙二醇、聚四氢呋喃醚二醇、聚氧四亚甲基二醇、四氢呋喃与环氧乙烷的共聚二醇、聚（氧基-1，2-丙烯）二醇、蓖麻油多元醇中的一种或多种。
5.根据权利要求1-4任一项所述的方法，其特征在于，所述步骤（2）中，扩链剂为1，4-丁二醇、2，3-丁二醇、二甘醇、三羟甲基丙烷、山梨醇、2，2-二羟甲基丙酸、N-甲基二乙醇胺中的一种或多种。
6.根据权利要求1-5任一项所述的方法，其特征在于，所述的COF多孔材料，其制备方法包括以下步骤：将氨基芳香化合物、醛基羟基芳香化合物、催化剂、有机溶剂加热反应，抽滤，洗涤，干燥后即得到COF多孔材料。
7.根据权利要求6所述的方法，其特征在于，所述的氨基芳香化合物中，氨基取代基的个数至少为2，作为氨基芳香化合物的骨架，芳香单元选自苯基、联苯基、1,3,5-三苯基苯、1,3,5-三苯基-2,4,6-三嗪、1,2,3,4,5,6-六苯基取代苯、1,3,5-三(4-氨基苯基)苯、芴、螺二芴、芴酮、芘、三苯胺、噻吩、咔唑、苯并咪唑或四苯基乙烯；所述氨基芳香化合物优选的为1,3,5-三(4-氨基苯基)苯。
8.根据权利要求6或7所述的方法，其特征在于，所述的醛基羟基芳香化合物中，醛基取代基的个数至少为2，羟基取代基的个数为1-4，作为醛基羟基芳香化合物的骨架，芳香单元选自苯基、联苯基、1,3,5-三苯基苯、1,3,5-三苯基-2,4,6-三嗪、1,2,3,4,5,6-六苯基取代苯、芴、螺二芴、芴酮、芘、三苯胺、噻吩、咔唑、苯并咪唑或四苯基乙烯；所述醛基羟基芳香化合物优选为2，5-二羟基-1，4-对苯二甲醛。
9.根据权利要求6-8任一项所述的方法，其特征在于，所述的醛基羟基芳香化合物中，醛基和羟基的基团数量比为1:1~1:0。
10.根据权利要求6-9任一项所述的方法，其特征在于，所述的反应温度为80~180℃，优选为100~120℃；反应时间为24~72h，优选为48~72h。
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