Active Utilization of Solvent-Mediated Transformation for Exclusive Production of Metastable Polymorph Crystals of AE1-923

JOURNAL OF CHEMICAL ENGINEERING OF JAPAN

Masaki Okamoto²  Masaya Hamano¹  Hiroshi Ooshima² 

[1] Fukui Research Institute, Ono Pharmaceutical Co., Ltd.;Department of Applied and Bioapplied Chemistry, Graduate School of Engineering, Osaka City University

关键词: Poor Solvent Crystallization;    Solvent-Mediated Transformation;    Polymorph;    Meta-Stable Polymorph;    Drug Substance;   

DOI  :  10.1252/jcej.37.95

来源: Maruzen Company Ltd

【 摘 要 】

References(10)Cited-By(4)A drug substance AE1-923 (4-[[2-[N-(5-Methylfuran-2-sulfonyl)-N-isopropylamino]-5-(trifluoromethyl)phenoxy]methyl]benzoic acid), which was developed for the indications of pollakiuria and pain, was crystallized from the solution prepared with a mixed solvent of ethanol and water. AE1-923 was found to have three kinds of crystal polymorphs in the mixed solvent; namely the unstable A-form, the meta-stable B-form, and the stable C-form. The method of reliable and exclusive production of the meta-stable crystals among the three kinds of crystals was investigated.Three kinds of crystallization operation were attempted. Operation-1 was designed for directly precipitating the B-form crystals by cooling crystallization without precipitating the unstable A-form crystals. However, it was failed by a rapid transformation of polymorph from the B-form to the C-form. Operation-2 was designed for actively utilizing the transformation of polymorph from the A-form crystals to the B-form crystals by cooling crystallization. However, this operation was also failed by the same reason, namely a rapid transformation to the stable C-form. Operation-3 was also designed for actively utilizing the transformation of polymorph by poor solvent crystallization. By Operation-3, each polymorph including the B-form could be exclusively and consecutively produced. From these results, it was concluded that the utilization of the solvent-mediated transformation from the unstable polymorph to the meta-stable polymorph is effective for the production of meta-stable crystals even when three kinds of polymorphs may be simultaneously precipitated.

【 授权许可】

Unknown