CN116041275A - 一种利可君的晶型a及其制备方法、用途 - Google Patents
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Abstract
本发明涉及化合物晶型领域,具体涉及一种利可君晶型A及其制备方法、用途。本发明的技术方案以水和N,N‑二甲基甲酰胺为溶剂、使利可君形成晶型A,具有稳定性好、水中溶解度高、生物吸收利用度好的优点。
Description
技术领域
本发明属于药物化学晶体制备技术领域,具体涉及一种利可君的晶型A,还涉及所述晶型A的制备方法以及用途。
背景技术
利可君是一种典型的噻唑羧酸类升白药物,其化学名为2-(α-苯基-α-乙氧羰基-甲基)噻唑烷-4-羧酸,对白细胞有促进增生作用,被广泛应用于放射疗法和化学疗法治疗恶性肿瘤过程中引起的白细胞减少症的治疗。利可君为半胱氨酸衍生物,服用后迅速被吸收,从而增强机体造血系统的功能,目前多用于预防和治疗各种原因引起的白细胞减少、再生障碍性贫血及血小板减少症等。
一般制备4-羧酸噻唑烷及其衍生物的方法是用L-半胱氨酸盐酸盐和相应的醛在适当的条件下缩合而成,具体到利可君则是由苯乙酸乙酯在醇钠的存在下与甲酸乙酯反应,生成α-甲酰基苯乙酸乙酯,然后再与L-半胱氨酸盐酸盐进行环合而成,产品在室温条件下析出,经过滤、洗涤、重结晶即得,产品为白色晶状粉末,难溶于水和乙醇。
申请号为CN200410054101.3的专利申请中公开了由苯乙酸乙酯、甲酸乙酯、乙醚、金属钠经过缩合、酸化、环合制备得到利可君原料,其中详细记载了在环合步骤中控制pH在7左右、反应物在水和乙醇存在下加热回流后冷却结晶、甩滤,结晶用蒸馏水、乙醇先后洗涤,再用少量乙醚洗涤的晶体制备及纯化方法。
申请号为CN200610037819.0的专利申请中公开的合成工艺是将苯乙酸乙酯、甲酸乙酯在缩合剂的作用下,经缩合、酸化而得甲酰基苯乙酸乙酯,甲酰基苯乙酸乙酯和半胱氨酸通过环合而成利可君原药,其原料药晶体的制备及纯化方法与前述方法基本相同,用于洗涤结晶的溶剂不同,为乙醚、乙醇和水。
申请号为CN201110357853.7的专利申请中公开了使苯乙酸乙酯、甲酸乙酯在特定溶剂和缩合剂存在下进行缩合反应,反应液经萃取纯化后酸化,然后低温析晶获得高纯度的固体中间体α-甲酰基苯乙酸乙酯,再与L-半胱氨酸盐酸盐在水和丙酮存在下进行反应,反应完成后冷却、抽滤、用水和丙酮反复洗涤,真空干燥得到产品。
另外还有傅霖等报道了分别用水、乙醇洗涤产物的方法。王艳霞等报道了在水和乙醇存在下反应得产物经过滤,滤饼分别用水、石油醚洗涤后干燥制得白色结晶状利可君的方法,产物熔点158.1-158.7℃。陆强、王艳艳报道了将含有水和乙醇的反应液加热回流后冷却至15-18℃,加入水搅拌6小时待充分析出产物后过滤、用乙醇、水(pH为3.0)、乙醇洗涤的方法。赵玲、杨博报道了以水和乙醇为溶剂制得反应产物,将反应产物冷却结晶,结晶用乙醚、乙醇和水洗涤后过滤,干燥得到产物的方法。
尽管利可君对于各种原因引起的白细胞减少症、血小板减少症、再生障碍性贫血等血液系统疾病的预防和治疗有着诸多的优点,但在实际应用中仍面临着一些问题:
1)利可君现有的晶型有一种特殊的气味,对病人用药的依从性有一定的影响;
2)利可君常用的晶型堆密度较小,对药物的释放有一定的影响;
3)利可君中含有甲酯杂质,会对药效产生影响,超过0.1%则不符合用药要求。
以上缺陷限制了其进一步临床推广和使用。因此,如何能够简单有效的改善其以上性质,对于利可君进一步发展及应用是极为关键的因素。而目前常用的改善其性质的方法,通常需要改变其结构、或添加助剂等方式,不仅成本较高,而且效果不确定。因此,在针对利可君的药物研发过程中亟需解决以上问题。
发明内容
本发明的目的在于克服现有技术中因戊唑醇中含有甲酯杂质及有特殊气味、水溶性不佳的问题,本发明的技术方案以水和N,N-二甲基甲酰胺为溶剂制备得到晶型A,具有水溶解度值高、水溶解速率高的优点,适合应用于药物制剂生产过程中。化学结构相同的药物因结晶条件不同而得到不同晶体,不同的晶体通常具有不同的理化性质,给制剂开发提供更多的选择性。
本发明为了实现上述技术目的,提供如下技术方案:一种利可君的晶型A,其X射线粉末衍射图谱在下列2θ角中的至少三处具有衍射峰:6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,29.390°±0.2。
进一步地,其X射线粉末衍射图谱在下列2θ角中的至少四处具有衍射峰:6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,29.390°±0.2。
进一步地,其X射线粉末衍射图谱在下列2θ角中的至少五处具有衍射峰:4.839°±0.2,6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,18.625°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,25.020°±0.2,26.341°±0.2,27.079°±0.2,28.088°±0.2,29.390°±0.2,31.200°±0.2,37.996°±0.2。
进一步地,其X射线粉末衍射图谱在下列2θ角的至少七处具有衍射峰:4.839°±0.2,6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,18.625°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,25.020°±0.2,26.341°±0.2,27.079°±0.2,28.088°±0.2,29.390°±0.2,31.200°±0.2,37.996°±0.2。
进一步地,熔点为161-162℃。
本发明还提供了如上所述的利可君的晶型A的制备方法,将利可君在N,N-二甲基甲酰胺存在的条件下搅拌溶解,降温、水析、抽滤、洗涤得滤饼,干燥得到所述晶型A。
进一步地,所述溶解及搅拌的温度均不高于15℃。
再进一步地,所述溶解及搅拌的温度为8-12℃。
进一步地,所述水和N,N-二甲基甲酰胺的体积比为1:1。
进一步地,所述干燥为在60-80℃条件下鼓风干燥。
再进一步地,所述干燥为在70℃条件下鼓风干燥。
本发明还提供了一种药物组合物,包括有效量的如上所述的利可君晶型A。
再进一步地,还包括药学上可接受的辅料。
本发明还提供了如上所述的利可君晶型A或如上所述的药物组合物在制备用于预防和治疗血液系统疾病的药物中的用途。
进一步地,所述血液系统疾病为各种原因引起的白细胞减少症、血小板减少症、再生障碍性贫血。
由于采用了以上技术,本发明与现有技术相比,其显著优点为:
1)本发明的技术方案以水和N,N-二甲基甲酰胺为溶剂在低温条件下制备得到利可君晶型A,具有水溶解度值高、水溶解速率高的优点,尤其是将水中溶解度提高到了240μg/ml以上,并且大大降低了杂质含量,适合应用于药物制剂生产过程中,解决了现有技术中因利可君较低的水溶性而导致的制剂制备及储存过程中产生的不便;
2)本发明的利可君晶型A与常规的利可君原药晶型相比具有更佳的生物活性,更适合应用于药物制剂中。
附图说明
图1为本发明的利可君晶型A的XRPD图谱。
图2为本发明的利可君晶型B的XRPD图谱。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明,但不应该将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容实现的技术均属于本发明的范围。
XRPD测定方法
XRPD测试使用PANalytical公司的X’Pert3型X射线衍射仪。将适量样品均匀平铺在单晶硅样品盘上,用以下描述参数进行XRPD测试:
表1 XRPD实验参数
TGA及DSC测定方法
TGA及DCS图谱分别在TADiscovery TGA 5500热重分析仪及TADiscovery DSC2500差示扫描量热仪上采集,试验参数如下:
表2 TGA及DSC试验参数
TGA | DSC | |
样品盘 | 铝盘,开盖 | 铝盘,开盖 |
温度范围/℃ | RT-~190~205 | 25-~190 |
扫描速率/℃min | 10 | 10 |
保护气体 | 氮气 | 氮气 |
实施例1
本实施方式的利可君晶型A的制备方法按以下步骤实施:
称取2g利可君原料药用25mLN,N-二甲基甲酰胺于三口瓶中溶解,置于冰水浴中降温,开启搅拌。当反应瓶内温约10℃时,量取25mL纯化水滴加到反应瓶中,过程控制温度10±2℃。滴加结束后保温搅拌15~20分钟,抽滤。滤饼分别用20mL冰纯化水打浆洗涤2遍,淋洗1遍,于70℃鼓风干燥,得利可君A晶型粉末1g,未检出利可君甲酯杂质(低于0.01%)。其XRPD图谱如图1所示,具体衍射峰数据如表3所示。熔点:161-162℃。
表3 XRPD衍射峰数据
实施例2
本实施方式的利可君晶型C的制备方法按以下步骤实施:
称取2g利可君原料药用25mL乙醇于三口瓶中溶解,置于冰水浴中降温,开启搅拌。当反应瓶内温约10℃时,量取25mL纯化水滴加到反应瓶中,过程控制温度10±2℃。滴加结束后保温搅拌15~20分钟,抽滤。滤饼分别用20mL冰纯化水打浆洗涤2遍,淋洗1遍,于70℃鼓风干燥,得利可君C晶型粉末0.5g,利可君甲酯杂质含量为0.09%。熔点:157-158℃。
实施例3
利可君晶型A及C的TGA/DCS数据如下表所示:
表4利可君晶型A及C的TGA/DCS试验结果
样品组别 | DSC吸热峰(峰值温度,℃) | TGA失重(%) |
晶型A | 132.8,160.5,164.6,169.1 | 2.07(100℃) |
晶型C | 95.2,107.8 | 3.54(70℃) |
上表显示,利可君晶型A的热稳定性相对于晶型C较佳。
实施例4
利可君晶型A及C的水饱和溶解度试验数据如下表所示:
表5利可君晶型A及C的水饱和溶解度试验结果
样品组别 | 1小时溶解度(μg/ml) | 2小时溶解度(μg/ml) | 18小时溶解度(μg/ml) |
晶型A | 115.33 | 137.28 | 241.02 |
晶型C | 112.64 | 133.16 | 227.89 |
上表显示,利可君晶型A的溶解性能相对于晶型C较佳。
实施例5
选用Balb/c小鼠,雄性,体重范围22~24g,随机选择100只并随机分为5组,分别为正常对照组、模型对照组、利可君晶型A组、利可君晶型B组、利可君晶型C组,每组20只。利可君A、B和C组共灌胃给药28天,每天1次,每次30mg/kg;正常对照组和模型对照组给予等体积生理盐水。环磷酰胺于第8~14天时腹腔注射25mg/kg造模(模型组、利可君组)。灌胃28天。分别于造模前、造模后以及给药结束后(即给药后第7天、第15天、第29天)取眶后静脉窦血检测白细胞数。统计学处理实验数据均以均数士标准差表示,应用SPSS17.0软件包进行统计学处理,以P<0.05为有统计学意义。结果见下表。
注:与模型对照组比较,*P<0.05;与利可君C组比较,△P<O.05
上表显示,造模各组小鼠外周血白细胞数明显减少,均少于4.0×109/L,表明造模成功。经治疗后,利可君晶型A、B、C组均可显著升高白细胞含量,与模型对照组比较均具有显著性差异(P<0.05);其中利可君晶型A、B组效果较好,与利可君晶型C组比较具有显著性差异(P<0.05)。
上述实施例仅为本发明的优选技术方案,而不应视为对于本发明的限制,本发明的保护范围应以权利要求记载的技术方案,包括权利要求记载的技术方案中技术特征的等同替换方案为保护范围,即在此范围内的等同替换改进,也在本发明的保护范围之内。
Claims (10)
1.一种利可君的晶型A,其特征在于,其X射线粉末衍射图谱在下列2θ角中的至少三处具有衍射峰:6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,29.390°±0.2。
2.根据权利要求1所述的晶型A,其特征在于,其X射线粉末衍射图谱在下列2θ角中的至少四处具有衍射峰:6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,29.390°±0.2。
3.根据权利要求2所述的晶型A,其特征在于,其X射线粉末衍射图谱在下列2θ角中的至少五处具有衍射峰:4.839°±0.2,6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,18.625°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,25.020°±0.2,26.341°±0.2,27.079°±0.2,28.088°±0.2,29.390°±0.2,31.200°±0.2,37.996°±0.2。
4.根据权利要求1~3任一项所述的晶型A,其特征在于,其X射线粉末衍射图谱在下列2θ角的至少七处具有衍射峰:4.839°±0.2,6.215°±0.2,9.738°±0.2,13.130°±0.2,18.072°±0.2,18.625°±0.2,19.516°±0.2,21.446°±0.2,22.331°±0.2,23.688°±0.2,25.020°±0.2,26.341°±0.2,27.079°±0.2,28.088°±0.2,29.390°±0.2,31.200°±0.2,37.996°±0.2。
5.根据权利要求4所述的晶型A,其特征在于,熔点为161-162℃。
6.一种如权利要求1所述的利可君的晶型A的制备方法,其特征在于,将利可君在N,N-二甲基甲酰胺存在的条件下搅拌溶解,降温、水析,抽滤洗涤得滤饼,干燥得到所述晶型A。
7.根据权利要求6所述的制备方法,其特征在于,所述溶解及搅拌的温度均不高于15℃;
所述水和N,N-二甲基甲酰胺的体积比为1:1;
所述干燥为在60-80℃条件下鼓风干燥。
8.一种药物组合物,其特征在于,包括有效量的如权利要求1-7任一项所述的利可君晶型A;优选的,还包括药学上可接受的辅料。
9.权利要求1-5中任一项所述的利可君晶型A或权利要求8所述的药物组合物在制备用于预防和治疗血液系统疾病的药物中的用途。
10.如权利要求9所述的用途,所述血液系统疾病为各种原因引起的白细胞减少症、血小板减少症、再生障碍性贫血。
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