(606c) The Understanding of Nucleation Aspects of Tolbutamide Polymorphs in Solution

The understanding of nucleation aspects of tolbutamide polymorphs in Solution

Yin Yani,*^† Pui Shan Chow,^† and Reginald B. H. Tan^†,‡

^† Institute of Chemical & Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833

^‡ Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576

* Corresponding author. Tel: (65) 6796 3852. Email: yin_yani@ices.a-star.edu.sg

Abstract

Experimental works^{1, 2} have shown that tolbutamide (TB) Form I is preferentially nucleated from solution. Raman spectra collected for TB solute in saturated solution closely matches with that of TB Form I in suspension². This observation shows that there could be some unique interactions of tolbutamide molecules or solvent molecules in solution that eventually lead to the nucleation of TB Form I. We use molecular dynamics simulation to observe the conformations and arrangements of tolbutamide molecules in saturated and supersaturated solutions. Various solvents were considered in the simulations, such as, ethanol, methanol, and acetonitrile. The simulation results show that, at pre-nucleation stage, TB molecules in solutions arranged close to the structure of TB Form I in vacuum. In addition to that, our simulation has determined that majority of the single TB molecules in solutions arrange more like the type of TB conformation found in Form I.    

References                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   

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2.         Thirunahari, S.; Chow, P. S.; Tan, R. B. H., Quality by Design (QbD)-Based Crystallization Process Development for the Polymorphic Drug Tolbutamide. Crystal Growth & Design 2011, 11 (7), 3027-3038.