WO2021238088A1 - N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途 - Google Patents
N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物及其制备方法和用途 Download PDFInfo
- Publication number
- WO2021238088A1 WO2021238088A1 PCT/CN2020/128050 CN2020128050W WO2021238088A1 WO 2021238088 A1 WO2021238088 A1 WO 2021238088A1 CN 2020128050 W CN2020128050 W CN 2020128050W WO 2021238088 A1 WO2021238088 A1 WO 2021238088A1
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- WIPO (PCT)
- Prior art keywords
- crystal form
- hydroxybenzoyl
- amino
- potassium
- octanoate
- Prior art date
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- 239000013078 crystal Substances 0.000 title claims abstract description 505
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims abstract description 239
- 238000002360 preparation method Methods 0.000 title claims abstract description 56
- RLEFZEWKMQQZOA-UHFFFAOYSA-M potassium;octanoate Chemical compound [K+].CCCCCCCC([O-])=O RLEFZEWKMQQZOA-UHFFFAOYSA-M 0.000 title claims abstract description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 134
- 230000003449 preventive effect Effects 0.000 claims abstract description 22
- 229940126585 therapeutic drug Drugs 0.000 claims abstract description 22
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 193
- 239000011591 potassium Substances 0.000 claims description 193
- 229910052700 potassium Inorganic materials 0.000 claims description 193
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 180
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 60
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
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Abstract
Description
组别 | 采血时间点 |
静脉注射M4组 | 给药前0小时,给药后0.5、1、3、6、12、24、48、72、96、144和192小时; |
口服给药组 | 给药前0小时,给药后1.5、3、8、24、48、72、96小时 |
组别 | 给药途径 | 给药剂量 | 动物数量(只) |
M4 | i.v. | 0.05mg/kg | 4 |
SNAC(300mg)+M4 | p.o. | 300+10mg片剂1片 | 4 |
SNAC(450mg)+M4 | p.o. | 450+10mg片剂1片 | 4 |
PNAC-Ⅰ(300mg)+M4 | p.o. | 300+10mg片剂1片 | 4 |
PNAC-Ⅰ(450mg)+M4 | p.o. | 450+10mg片剂1片 | 4 |
PNAC-IⅠ(300mg)+M4 | p.o. | 300+10mg片剂1片 | 4 |
PNAC-IⅠ(450mg)+M4 | p.o. | 450+10mg片剂1片 | 4 |
组 | 血药浓度(nM)-给药时间(h) |
别 | 0h | 0.5h | 1h | 3h | 6h | 12h | 24h | 48h | 72h | 96h | 144h | 192h |
M4 | 0 | 165.48 | 148.39 | 130.11 | 112.59 | 99.76 | 80.12 | 58.29 | 38.03 | 26.48 | 12.10 | 4.89 |
Claims (47)
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I,所述晶型I至少具有2θ°为:7.83±0.2、26.64±0.2、18.89±0.2表示的特征峰的X射线粉末衍射图。
- 根据权利要求1所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型I至少还具有2θ°为:5.24±0.2、21.59±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求2所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型I至少还具有2θ°为:13.02±0.2、24.29±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求3所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型I至少还具有2θ°为:6.61±0.2、10.43±0.2、31.63±0.2、37.00±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型I的X射线粉末衍射图如图1。
- 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型I的熔点为163.1℃。
- 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型I的吸附水脱除温度为83.6℃。
- 根据权利要求1-4任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型I在140℃失重3.0%。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型II,所述晶型II至少具有2θ°为:24.76±0.2、6.73±0.2、20.26±0.2表示的特征峰的X射线粉末衍射图。
- 根据权利要求9所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型II至少还具有2θ°为:14.68±0.2、25.55±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求10所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型II至少还具有2θ°为:13.41±0.2、26.66±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求11所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型II至少还具有2θ°为:21.08±0.2、25.79±0.2、28.47±0.2、12.07±0.2、15.38±0.2、23.38±0.2、29.48±0.2、22.55±0.2、27.79±0.2、8.91±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求9所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型II的X射线粉末衍射图如图3。
- 根据权利要求9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型II的熔点为162.5℃。
- 根据权利要求9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型II的吸附水脱除温度为93℃。
- 根据权利要求9-13任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型II在140℃失重5.6%。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型III,所述晶型III至少具有2θ°为:9.06±0.2、23.30±0.2、21.44±0.2表示的特征峰的X射线粉末衍射图。
- 根据权利要求17所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型III至少还具有2θ°为:24.75±0.2、6.03±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求18所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型III至少还具有2θ°为:21.20±0.2、17.06±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求19所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型III至少还具有2θ°为:21.75±0.2、29.52±0.2、22.15±0.2、15.11±0.2、28.47±0.2、22.54±0.2、30.71±0.2、17.91±0.2、15.64±0.2、26.49±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求17所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型III的X射线粉末衍射图如图5。
- 根据权利要求17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型III的熔点为162.0℃。
- 根据权利要求17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型III的吸附水脱除温度为94.5℃。
- 根据权利要求17-21任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型III在140℃失重6.1%。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于, 所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型IV,所述晶型IV至少具有2θ°为:16.25±0.2、6.8±0.2、22.08±0.2表示的特征峰的X射线粉末衍射图。
- 根据权利要求25所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型IV至少还具有2θ°为:13.16±0.2、19.39±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求26所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型IV至少还具有2θ°为:18.35±0.2、9.68±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求27所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型IV至少还具有2θ°为:15.92±0.2、11.71±0.2、29.91±0.2、23.04±0.2、16.56±0.2、23.5±0.2、27.31±0.2、19.74±0.2、34.34±0.2、18.82±0.2之一表示的特征峰的X射线粉末衍射图。
- 根据权利要求25所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型IV的X射线粉末衍射图如图7。
- 根据权利要求25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型IV的熔点为163.8℃。
- 根据权利要求25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型IV的吸附水脱除温度为96.1℃。
- 根据权利要求25-29任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物,其特征在于,所述晶型IV在150℃失重8.21%。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶体多晶型物的制备方法,其特征在于,包括如下步骤:在反应容器中加入有机溶剂并搅拌,然后加入N-[8-(2-羟基苯甲酰基)氨基]辛酸,搅拌均匀,滴加氢氧化钾溶液,滴加完毕后,浓缩得粗品;在所述粗品中加入有机溶剂打浆抽滤后得滤饼,将所述滤饼淋洗后放入干燥箱中干燥,得到所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物。
- 根据权利要求33所述的制备方法,其特征在于,将所述滤饼淋洗后放入干燥箱中进行干燥,干燥温度为60℃~100℃,干燥时间为30~40h,得到所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I;优选地,所述干燥分两个步骤,先60℃进行干燥16h,后体系氮气平压后再次在100℃干燥24h;所述晶型I为权利要求1-8任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
- 根据权利要求33所述的制备方法,其特征在于,将所述滤饼制备成均匀的颗粒,然后再将所述颗粒放入所述干燥箱中进行干燥,干燥后的颗粒均匀地铺散在2-8℃的低温环境,控制相对湿度为50%放置2天,以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型III;所述颗粒放入所述干燥箱中的干燥温度为60℃~100℃,干燥时间为30~40h;优选地,所述干燥分两个步骤,先60℃进行干燥16h,后体系氮气平压后再次在100℃干燥24h;将所述滤饼过20~24目筛得到均匀的颗粒;所述晶型III为权利要求17-24任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型III。
- 根据权利要求33-35任一项所述的制备方法,其特征在于,所述有机溶剂为异丙醇或丙酮;所述氢氧化钾的溶液浓度为40%~90%,优选地所述氢氧化钾的溶液浓度为50%。
- 根据权利要求33-35任一项所述的制备方法,其特征在于,加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后,体系升温至48℃以上,然后滴加氢氧化钾溶液,滴加完毕后,保温反应0.5~2h;优选地,加入N-[8-(2-羟基苯甲酰基)氨基]辛酸后,体系升温至 48℃~52℃,然后滴加氢氧化钾溶液,滴加完毕后,保温反应1h;所述N-[8-(2-羟基苯甲酰基)氨基]辛酸以及氢氧化钾溶液的添加摩尔比为1:1;所述粗品加入有机溶剂打浆的时间为0.5~1.5h,优选为1h。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I的制备方法,其特征在于,将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型加热至至少75℃以上,以形成晶型I;所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上;将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型在氮气保护下加热至75℃以上,以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
- 根据权利要求38所述的制备方法,其特征在于,将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II在氮气保护下加热至140℃,以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
- 根据权利要求38所述的制备方法,其特征在于,将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV在氮气保护下加热至110℃以形成N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型I的制备方法,其特征在于,将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型冻干,以形成晶型I;所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型I以外的晶型为晶型II、晶型III、晶型IV中的至少一种或两种以上;所述晶型I为权利要求1-8任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型I。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II的制备方法,其特征在于,将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型,在 室温条件下,暴露于具有0~60%的相对湿度环境中,24h以上,以形成所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
- 根据权利要求42所述的制备方法,其特征在于,所述相对湿度为20%、30%、40%、60%的环境;所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型II以外的晶型为晶型I、晶型III、晶型IV中的至少一种或两种以上;所述晶型II为权利要求9-16任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型II。
- 一种N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶型IV的制备方法,其特征在于,包括如下步骤:将N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型,在高于80%的相对湿度环境中形成胶样物质;所述N-[8-(2-羟基苯甲酰基)氨基]辛酸钾除晶型IV以外的晶型为晶型I、晶型II、晶型III中的至少一种或两种以上;将所述胶样物质在室温条件下,暴露于具有20%~40%的相对湿度环境中,120h以上,以形成晶型IV;所述晶型IV为权利要求25-32任一项所述的N-[8-(2-羟基苯甲酰基)氨基]辛酸钾的晶型IV。
- 一种药物组合物,其特征在于,包括N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物;N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物为晶型I、晶型II、晶型III、晶型IV中的一种或至少两种。
- 根据权利要求45所述的药物组合物,其特征在于,所述药物组合物还包括预防和/或治疗性药物;所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的重量比为(20~60):1,优选地,所述药物组合物中N-[8-(2-羟基苯甲酰基)氨基]辛酸钾晶体多晶型物与预防和/或治疗性药物的 重量比为30:1。
- 根据权利要求46所述的药物组合物,其特征在于,所述预防和/或治疗性药物为胰高血糖素样肽-1、胰岛素、PYY、人胰淀素、肝素、人生长激素、干扰素、单克隆抗体、蛋白酶抑制剂、血小板生成素。
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