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Preparation of Theophylline-Benzoic Acid Cocrystal and On-Line Monitoring of Cocrystallization Process in Solution by Raman Spectroscopy

1
State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
2
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
3
Key Laboratory Modern Drug Delivery and High Efficiency in Tianjin University, Tianjin 300072, China
*
Authors to whom correspondence should be addressed.
Crystals 2019, 9(7), 329; https://doi.org/10.3390/cryst9070329
Received: 5 June 2019 / Revised: 23 June 2019 / Accepted: 25 June 2019 / Published: 27 June 2019
(This article belongs to the Special Issue Pharmaceutical Crystals)
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Abstract

Pure theophylline-benzoic acid cocrystal was prepared via slurry and cooling crystallization in solution to overcome the disadvantages of existing preparation methods. The target cocrystal was characterized by powder X-ray diffraction (PXRD), thermalgravimetric analysis (TGA), differential scanning calorimetry (DSC) and Raman spectroscopy. The slurry and cooling cocrystallization process in solution was monitored via on-line Raman spectroscopy. The results obtained from on-line Raman monitoring can exhibit the transformation process from raw materials (theophylline and benzoic acid) to cocrystal and show the cocrystal formation rate. Comparing each transformation process under different conditions in slurry crystallization, we found that suspension density of raw materials and temperature both have an impact on the theophylline-benzoic acid cocrystal formation rate. It could be concluded that the cocrystal formation rate increased with the increase of suspension density of raw materials. Further under the same suspension density, higher temperature will accelerate theophylline-benzoic acid cocrystal formation. Meanwhile, various data from the cocrystallization process in cooling crystallization, including nucleation time, nucleation temperature and suitable cooling ending point can be gained from results of on-line Raman monitoring. View Full-Text
Keywords: cocrystal; solution crystallization; Raman spectroscopy; on-line monitoring; cocrystal formation cocrystal; solution crystallization; Raman spectroscopy; on-line monitoring; cocrystal formation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Huang, Y.; Zhou, L.; Yang, W.; Li, Y.; Yang, Y.; Zhang, Z.; Wang, C.; Zhang, X.; Yin, Q. Preparation of Theophylline-Benzoic Acid Cocrystal and On-Line Monitoring of Cocrystallization Process in Solution by Raman Spectroscopy. Crystals 2019, 9, 329.

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