CN110143915A - 一种依托考昔与对甲苯磺酸形成盐的新晶型及制备方法 - Google Patents
一种依托考昔与对甲苯磺酸形成盐的新晶型及制备方法 Download PDFInfo
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Abstract
本发明公开一种选择性COX‑2抑制剂依托考昔与对甲苯磺酸形成具有药用功能性盐的晶型及其制备方法,属于药物新盐制备技术领域。本发明制备的依托考昔与对甲苯磺酸形成盐,经热失重(TGA)、X‑射线粉末衍射(P‑XRD)、X‑射线单晶衍射(S‑XRD)差示扫描量热(DSC)、紫外光谱(UV)以及核磁H谱(H‑NMR)等分析方法检测。由于依托考昔是一种难溶性药物,将依托考昔与对甲苯磺酸形成新盐应用在固体制剂中,具有良好的溶解度与稳定性,新盐型的开发,使其新剂型的开发与应用奠定了基础。
Description
技术领域
本发明属于药物新盐制备技术领域,具体涉及一种依托考昔与对甲苯磺酸形成盐的新晶型及制备方法。
背景技术
依托考昔是一种高选择性环氧化酶-2(COX-2)抑制药,英文名是Etoricoxib,化学名为[5-氯-2-(6-甲基吡啶-3基)-3-(4-甲基磺酰苯基)吡啶(5-Chloro-3-(4-methanesulfonyl-phenyl)-6’-methyl-[2,3’]bipyridinyl),分子式为C18H15ClN2O2S。
依托考昔用于治疗骨关节炎(OA)、类风湿关节炎和急性痛风性关节炎。依托考昔是一种镇痛药物,其性能较传统非甾体抗炎药(NSAIDs)有所提高,是唯一已经证实的治疗急性痛风性关节炎有效的昔布类药物。目前在墨西哥、巴西和秘鲁被批准的其它适应证还有:缓解拔牙后疼痛和原发性痛经,缓解慢性肌肉骨骼疼痛,包括慢性背痛等。
由于依托考昔的晶型对药物稳定性、溶解度、药理功能具有较大的影响,使新晶型依托考昔的开发逐渐成为药物新盐制备领域的研究热点之一;如申请号为CN201710474511.0的专利,公开一种制备依托考昔晶型V的方法;如申请号为CN201710877361.8的专利,公开一种邻苯二甲酸与依托考昔形成盐的晶型及其制备方法;如申请号为CN201710869983.6的专利,公开一种依托考昔与对硝基苯甲酸形成的盐的晶型及制备方法。但目前为止,尚未有以对甲苯磺酸为反应物与依托考昔合成盐晶的新晶型相关报道,有鉴于此,本发明在于提供一种依托考昔新的盐型及制备方法,具有良好的溶解度与稳定性,新的盐型开发,使其新剂型的开发与应用奠定了基础。
发明内容
针对现有技术的不足之处,本发明的目的在于提供一种依托考昔与对甲苯磺酸形成盐的新晶型及制备方法,该制备方法简单,重现性好。
本发明的技术方案概述如下:
一种依托考昔与对甲苯磺酸形成盐的新晶型:该药物共晶是以依托考昔作为药物活性成分,以对甲苯磺酸为反应物,两者按照1:(0.8~1.2)的摩尔比在甲醇或乙腈溶剂中反应成盐,其空间群为单斜晶系,依托考昔分子和对甲苯磺酸分子按1:1的比例成盐,通过成盐时形成的氢键结合在一起构成依托考昔与对甲苯磺酸形成新盐的基本单元。
本发明药物共晶的晶系属于单斜晶系,晶胞参数为:轴长轴角α=90°,β=112.32°,γ=90°;其X-射线粉末衍射图谱中,在晶面距d值为 处有衍射峰;其热失重谱图显示:熔点为224.5℃,在393.9℃完成分解过程;其在甲醇溶剂中紫外谱图的出峰位置,最大吸收峰为203.4nm和222.2nm;其核磁氢谱的位移:1H-NMR(500MHz,MeOD):δ2.34(s,3H),2.74(s,3H),3.13(s,1H),7.18(d,2H),7.57(d,2H),7.65(d,2H),7.76(d,1H),7.96(d,2H),8.08(d,1H),8.26(dd,1H),8.65(d,1H),8.80(d,1H)。
本发明还提供一种依托考昔与对甲苯磺酸形成盐的制备方法:在0~15℃下,将摩尔比为1:(0.8~1.2)的依托考昔和对甲苯磺酸加入到三角烧瓶中,按每1mmol依托考昔对应20ml溶剂的比例,分批次加入甲醇或乙腈溶剂,恒温搅拌,当溶液有轻微浑浊现象停止,在0~40℃静置,缓慢析出盐晶固体,过滤干燥,得到产品。
附图说明
图1为本发明依托考昔与对甲苯磺酸形成新盐的单晶结构;
图2为本发明依托考昔和对甲苯磺酸形成新盐的DSC和TG示意图;
图3为本发明依托考昔和对甲苯磺酸形成新盐的的粉末衍射示意图;
图4为本发明依托考昔和对甲苯磺酸形成新盐的紫外示意图;
图5为本发明依托考昔和对甲苯磺酸形成新盐的核磁氢谱示意图;
图6为本发明依托考昔和对甲苯磺酸形成新盐中有关物质对比色谱图。
本发明的有益效果:
本发明发现并制备了依托考昔与对甲苯磺酸的新盐型,经过测试在固体制剂制备的过程中具有良好的溶解度与稳定性,为其新剂型的开发与应用奠定了基础。
具体实施方式
下面结合实施例对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
实施例1制备依托考昔与对甲苯磺酸形成盐
在冰浴下,将依托考昔(358mg,1mmol)和对甲苯磺酸(0.8mmol)加入到50ml三角烧瓶中,分批次加入20ml甲醇,搅拌半小时后,当溶液有轻微浑浊现象停止搅拌,放置到10℃的防爆冰箱中,缓慢析出,过滤除去多余溶剂,洗涤、真空干燥,得到产品。
实施例2制备依托考昔与对甲苯磺酸形成盐
在冰浴下,将依托考昔(350mg,1mmol)和对甲苯磺酸(1.2mmol)加入到50ml三角烧瓶中,分批次加入20ml甲醇,当溶液有轻微浑浊现象,停止加入,搅拌半小时后,放置在0℃的防爆冰箱中,缓慢析出,过滤除去多余溶剂,洗涤、真空干燥,得到产品。
实施例3对实施例1所得盐晶产品进行高温试验测试
温度分别选择40℃、60℃两个温度水平:将实施例1所得盐晶样品在60℃温度下放置10天,于第5天和第10天取样,按稳定性重点考察项目进行检测;若样品无明显变化则不进行40℃条件下的试验;若样品有明显变化(如含量下降5%,鉴别不明显外观色泽变化大等),则须在40℃条件下同法进行试验。
实施例4对实施例1所得盐晶产品进行高湿试验测试
选择相对湿度为75%±5%、90%±5%两个湿度水平(T=25℃):将实施例1所得盐晶样品置于相对湿度90%±5%条件下(装KNO3饱和溶液的干燥器中,用封口胶密封)放置10天,于第5天和第10天取样,按稳定性重点考察项目要求检测,同时准确称量试验前后样品的重量,若样品无明显变化,则不进行75%±5%条件下的试验;若样品有明显变化(如含量下降5%,鉴别不明显,外观色泽变化大、吸湿重5%以上等),则须在相对湿度75%±5%条件下(装有NaCl饱和溶液的干燥器中,用凡士林密封)同法进行试验。
实施例5对实施例1所得盐晶产品进行强光照射试验测试
将实施例1所得盐晶样品放在装有日光灯的光照箱或其他适宜的光照装置内,于光照度为4500lx±500lx的条件下放置10天,于第5和第10天取样,按稳定性重点考察项目进行检测,特别要注意样品的外观变化。
实施例6一般条件下对实施例2所得盐晶产品进行稳定性试验测试
设置三组一般条件的稳定性试验,试验方法如下表所示:
试验 | 贮存条件 | 时间期限 |
长期试验 | 25℃±2℃/60%±5%RH | 12个月 |
长期试验 | 30℃±2℃/65%±5%RH | 6个月 |
加速试验 | 40℃±2℃/75%±5%RH | 6个月 |
采用HPLC检测实施例4-6处理后盐晶样品,检测结果如下表所示:
样品名 | 高温试验 | 高湿试验 | 光照试验 | 长期6月 | 长期12月 | 加速试验 |
依托考昔 | 99.90 | 99.88 | 99.91 | 99.92 | 99.90 | 99.90 |
盐晶 | 99.97 | 99.96 | 99.95 | 99.96 | 99.95 | 99.95 |
有关物质比较实验数据如下表所示,色谱图见图6:
综上所述,本发明制备出的新盐晶杂质含量和稳定性都相对较好,适合药物新剂型的开发。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节。
Claims (5)
1.一种依托考昔与对甲苯磺酸形成盐的新晶型,其特征在于:该药物共晶是依托考昔、对甲苯磺酸按照1:(0.8~1.2)的摩尔比反应形成的;其空间群为单斜晶系,晶胞参数为:轴长 轴角α=90°,β=112.32°,γ=90°;其X-射线粉末衍射图谱中,在晶面距d值为 处有衍射峰。
2.根据权利要求1所述的一种依托考昔与对甲苯磺酸形成盐的新晶型,其特征在于:该药物共晶的热失重谱图显示:熔点为224.5℃,在393.9℃完成分解过程。
3.根据权利要求1所述的一种依托考昔与对甲苯磺酸形成盐的新晶型,其特征在于:该药物共晶在甲醇溶剂中紫外谱图的出峰位置,最大吸收峰为203.4nm和222.2nm。
4.根据权利要求1所述的一种依托考昔与对甲苯磺酸形成盐的新晶型,其特征在于:该药物共晶核磁氢谱的位移:1H-NMR(500MHz,MeOD):δ2.34(s,3H),2.74(s,3H),3.13(s,1H),7.18(d,2H),7.57(d,2H),7.65(d,2H),7.76(d,1H),7.96(d,2H),8.08(d,1H),8.26(dd,1H),8.65(d,1H),8.80(d,1H)。
5.一种依托考昔与对甲苯磺酸形成盐的制备方法,其特征在于:在0~15℃下,将摩尔比为1:(0.8~1.2)的依托考昔和对甲苯磺酸加入到三角烧瓶中,按每1mmol依托考昔对应20ml溶剂的比例,分批次加入甲醇或乙腈溶剂,恒温搅拌,当溶液有轻微浑浊现象停止,在0~40℃静置,缓慢析出盐晶固体,过滤干燥,得到产品。
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