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1118626 
Journal Article 
Operation design for controlling polymorphism in the anti-solvent crystallization by using ternary phase diagram 
Takiyama, H; Minamisono, T; Osada, Y; Matsuoka, M 
2010 
Yes 
Chemical Engineering Research and Design
ISSN: 0263-8762
EISSN: 1744-3563 
88 
9A 
1242-1247 
WOS:000282246600018 
In the pharmaceutical production, to control polymorph formation is important from the viewpoint of the productivity and the bioavailability. Anti-solvent or drowning-out crystallization is widely used in the pharmaceutical industry for high yield production. However, anti-solvent addition method to control polymorph formation in anti-solvent crystallization has not been discussed enough. In this study, indomethacin (IMC) which has three polymorphs was used. The purpose of this study is to establish a production method of the target polymorph in the anti-solvent crystallization (IMC-acetone-heptane system). The simulation model for determination of anti-solvent feed rate based on the ternary phase diagram was proposed. The stability of the polymorph of IMC crystal in the solution was changed not only with temperature but also with composition of the mixed solvent. From the experimental and simulation results, the design strategy of anti-solvent crystallization was proposed. (C) 2009 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved. 
Anti-solvent; Polymorphism; Ternary phase diagram 
• Methanol (Non-Cancer)
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