瑞戈非尼结晶工艺研究.pdfVIP

瑞戈非尼结晶工艺研究

12*

李宏名，张娇(1.国药集团川抗制药有限公司，成都

611731；2.四川科伦药物研究院有限公司，成都

611138)

摘要：目的

优化瑞戈非尼结晶工艺，以控制基因毒性杂质含量。方法测定粗品在不同溶剂中的溶解度以及不同溶剂中

基因毒性杂质的增长情况，确定结晶溶剂体系和结晶方式；采用悬浮转晶试验和FBRM在线监测结晶过程确定目标晶型

的结晶工艺条件；采用研磨的方式研究择优取向；采用考察养晶过程中的液相浓度变化和固相形貌变化来控制养晶时间。

结果确定了瑞戈非尼Form

Ⅰ晶型的结晶工艺。结论优化后的结晶工艺产品中基因毒性杂质含量低，晶型纯度高，工

艺参数易于控制，适宜工业化生产。

关键词：瑞戈非尼；基因毒性杂质；择优取向；悬浮转晶试验；养晶时间

中图分类号：R914.4文献标志码：B文章编号：1007-7693(2025)05-0754-06

DOI:10.13748/ki.issn1007-7693

引用本文：李宏名,

张娇.

瑞戈非尼结晶工艺研究[J].

中国现代应用药学,

2025,

42(5):

754-759.

CrystallizationProcessStudyofRegorafenib

12*

LI

Hongming,

ZHANG

Jiao(1.SinopharmChuankangPharmaceuticalCo.,Ltd.,Chengdu611731,China;2.SichuanKelun

PharmaceuticalResearchInstituteCo.,Ltd.,Chengdu611138,China)

ABSTRACT:OBJECTIVE

To

optimize

crystallization

process

of

regorafenib

to

control

the

content

of

genotoxic

impurities.

METHODSThe

solubility

of

the

crude

product

and

the

increase

of

genotoxic

impurities

in

different

solvents

were

determined

to

identify

the

crystallization

solvent

system

and

crystallization

mode.

Suspension

transformation

experiments

and

FBRM

online

monitoring

were

used

to

determine

the

crystallization

process

conditions

for

the

target

crystal

form.

Grinding

was

employed

to

study

preferred

orientation.

The

changes

in

liquid

phase

concentration

and

solid

phase

morphology

during

crystal

maturation

were

investigated

to

control

the

ripening

time.

RESULTS

The

crystallization

process

for

Regorafenib

Form

Ⅰ

had

been

established.

CONCLUSIONThe

optimized

crystallization

process

yields

a

product

with

low

genotoxic

impurity

content,

high

crystal

form

purity,

and

easily

controllable

process

parameters,

making

it

suitable

for

industrial

production.

KEYWORDS:regorafenib;

genotoxic

impurities;

preferred

orientation;

suspension

transformation

experiments

;

ripening

time

瑞戈非尼(regorafenib，1)，商品名：拜万戈(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺(2)

(Stivarga)，化学名：4-[4-[