Theophylline Polymorph Control by High-Pressure Pure CO2 via Its Monohydrate

• Published in: Crystal growth & design 2022-01, Vol.22 (1), p.159-166
• Main Authors: Hao, Yingquan, Gong, Crystal, Kobayashi, Kinari, Akiyama, Seika, Shimoyama, Yusuke
• Format: Article
• Language: English
• ISSN: 1528-7483; 1528-7505
• DOI: 10.1021/acs.cgd.1c00718

Form V of theophylline, which can only be obtained with supercritical CO2 antisolvent processes as reported before, was achieved through the interaction between supercritical CO2 and theophylline monohydrate. We use supercritical CO2 to treat the theophylline monohydrate powder for 2 h as a batch process. As a result, a mixture of theophylline form II, form V, and monohydrate was obtained. We then studied the effects of pressure and temperature of supercritical CO2 on the formation of form V. Semiquantification based on powder X-ray diffraction indicated that the formation of form V favors a higher pressure while the temperature is fixed at 40 °C. Moreover, when the processing temperature is changed to 60 °C, only form II can be obtained. This suggests that the polymorph of theophylline can be easily controlled by verifying the condition of the supercritical CO2 treatment. In addition, we studied the dissolution behavior of the mixture obtained by our process and found the concentration of theophylline in water is slightly improved compared with form II. This is the first reported formation of form V induced by the interaction between theophylline monohydrate and supercritical CO2.