当前位置: X-MOL 学术Cryst. Growth Des. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Improving the Dissolution Rate of the Anticancer Drug Dabrafenib
Crystal Growth & Design ( IF 3.8 ) Pub Date : 2020-01-10 , DOI: 10.1021/acs.cgd.9b01365
Sunil K. Rai 1 , Anilkumar Gunnam 2 , M. K. Chaitanya Mannava 2 , Ashwini K. Nangia 1, 2
Affiliation  

Dabrafenib (DBF) is an anticancer drug with selective B-Raf (BRAF) inhibition activity. In 2013, DBF was approved by the U.S. Food and Drug Administration (US-FDA) as a dabrafenib mesylate salt (DBF·MS). Because of insolubility in aqueous medium, specifically at the pH 4–8 biorelevant range, DBF is a Biopharmaceutics Classification System (BCS) Class II drug (i.e., low solubility and high permeability). Therefore, screening of novel salts and cocrystals was carried out using Generally Recognized as Safe (GRAS) coformers. A total of 10 salts/cocrystals including the mesylate salt were found to be stable under the crystallization conditions. Among acidic coformers, methane sulfonic acid (MS) and saccharin (SACH) formed salts, while fumaric acid (FA), succinic acid (SA), and adipic acid (ADA) gave cocrystals. However, monoamines formed a monohydrate salt where the water molecule is hydrogen bonded with the aminopyrimidine moiety of DBF. The replacement of monoamines with ethylenediamine (EN) dislocated the water molecule near the free amine of EN in the crystal structure with a change in space group from triclinic (P1̅) to monoclinic (P21/n). Dissolution measurements at pH 1.2 (0.1 N HCl) showed that DBF·EN⊃H2O dissolved rapidly compared to the DBF·MS salt (the dissolution rate of DBF·EN⊃H2O and DBF·MS is 11 and 2 times faster than that of DBF). Structure–activity relationship analysis showed that bonding of the aminopyrimidine moiety with strong hydrogen bond synthons inhibited dissolution, whereas a loosely bound or free site at the aminopyrimidine moiety enhanced the dissolution rate. Finally, a cytotoxicity study was performed for DBF, DBF·MS, and DBF·EN⊃H2O, which showed that DBF·EN⊃H2O is safe for normal cells and yet equally potent against cancer cells. Crystal engineering of an improved formulation of dabrafenib·ethylenediamine hydrate is presented as a new anticancer drug.

中文翻译:

提高抗癌药物达布拉非尼的溶出度

达布拉非尼(DBF)是一种具有选择性B-Raf(BRAF)抑制活性的抗癌药物。2013年,DBF被美国食品和药物管理局(US-FDA)批准用作达拉非尼甲磺酸盐(DBF·MS)。由于在水性介质中不溶,特别是在pH 4-8与生物有关的范围内,DBF是生物制药分类系统(BCS)II类药物(即低溶解度和高渗透性)。因此,使用通常公认的安全(GRAS)共形成剂进行新型盐和共晶体的筛选。发现总共10个盐/包括甲磺酸盐的共晶体在结晶条件下是稳定的。在酸性共聚体中,甲烷磺酸(MS)和糖精(SACH形成盐,而富马酸(FA),琥珀酸(SA)和己二酸(ADA)生成共晶体。然而,单胺形成一水合物盐,其中水分子与DBF的氨基嘧啶部分氢键合。用乙二胺(EN)取代单胺使水分子在晶体结构中的EN游离胺附近移位,空间群从三斜(P 1ic)变为单斜(P 2 1 / n)。测量溶解在pH 1.2(0.1N盐酸)显示DBF·EN⊃H 2 ö迅速溶解相比DBF·MS盐(的溶解率DBF·EN⊃H 2 öDBF·MS比快11倍和2倍DBF)。结构-活性关系分析表明,氨基嘧啶部分与强氢键合子的键合会抑制溶解,而氨基嘧啶部分上的松散结合或自由位点会提高溶解速度。最后,对于进行了细胞毒性研究DBFDBF·MS,和DBF·EN⊃H 2 ö,表明DBF·EN⊃H 2 ö对正常细胞安全,但对癌细胞同样有效。达巴非尼·乙二胺水合物的改进配方的晶体工程学被认为是一种新的抗癌药物。
更新日期:2020-01-10
down
wechat
bug