How Many Parameters Can Affect the Solid Form of Cocrystallization Products in Mechanochemical Reactions? A Case Study

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1 Supporting Information How Many Parameters Can Affect the Solid Form of Cocrystallization Products in Mechanochemical Reactions? A Case Study Yue Yuan, a,b Lin Wang, a Duanxiu Li, a Zongwu Deng, a Hailu Zhang* a a Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Science, Suzhou , P.R. China. hlzhang2008@sinano.ac.cn; Fax: b School of pharmacy, Xi an Jiaotong University, Xi an , P.R. China. 1

2 Table of Contents Content Materials and methods Materials 3 Preparation of THP form IV 3 Preparation of AH form II 3 Single crystal of THP-AH11 3 Mechanochemical synthesis of THP-AH cocrystals 3 Powder X-ray diffraction (powder XRD) 3 Single crystal X-ray diffraction (single crystal XRD) 4 Figures Figure S1 Simulated powder XRD pattern of THP-AH12, and experimental pattern of THP-AH12 obtained via neat grinding manually. Figure S2 Simulated powder XRD patterns of THP form II, THP-AH12, and typical experimental pattern of co-grinding products of 1:1 THP II and AH I using a mortar and pestle. Figure S3 Simulated powder XRD patterns of THP-AH11 and THP-AH12. Experimental XRD patterns of ethanol-assisted grinding products of 1:1 THP II and AH I in a ball milling experiment using different reaction times: 5 min, 10 min (d), and 20 min (e). Figure S4 Simulated powder XRD patterns of THP-AH11 and THP-AH12. Experimental powder XRD pattern for the ethanol-assisted co-grinding product of THP-AH12, THP-AH11, and THP form II using a ball mill. Figure S5 Simulated powder XRD patterns of THP-AH11 and THP-AH12. Experimental patterns of ethanol-assisted grinding products of 1:2 THP II and AH I in a ball mill using different reaction times: 30 s, 5 min (d), and 20 min (e). Figure S6 The simulated (a, c) and experimental (b, d) powder XRD patterns of AH form I (a, b) and form II (c, d). Figure S7 Simulated powder XRD patterns of THP form II, AH form II, THP-AH11, and THP-AH12 (d). Experimental patterns of ethanol-assisted grinding products of 1:1 THP II and AH II in a ball mill using different reaction times: 5 min (e), 20 min (f). References 8 Page

3 Materials THP ( 99%, form II), was purchased from Adamas Reagent Co., Ltd. Potassium salt of Acesulfame (AK, 99.9%) was sourced from Xiya Chemical Reagent Co., Ltd. The free acid form of Acesulfame, AH (form I), was obtained by following the procedure reported by Velaga 1. All analytical grade solvents were obtained from Sinopharm Chemical Reagent Company and used as received without further purification. Preparation of THP form IV Form IV is the most thermodynamically stable anhydrous polymorph of THP. Powder sample of THP form IV was prepared by slurrying of excess THP form II in methanol for 7 days. 2 Preparation of AH form II AH form I was sealed in a vacuum glass tube and heated at 130 o C for 5 min. Then the melted sample was rapidly quenched using liquid nitrogen. This product was ground with dichloromethane at 40 Hz for 20 min in a ball mill (Pulverisette 23, Fritsch). Single crystal of THP-AH11 THP (form II, 0.2 mmol) and AH (form I, 0.2 mmol) were dissolved in 50 ml of toluene. The resulting solution was filtered through 0.22 μm PTFE syringe filter and left to slowly evaporate at room temperature. Colorless crystal of THP-AH11 can be picked out from the crystalline solids after 3 weeks. Mechanochemical synthesis of THP-AH cocrystals Generally, about 137 mg of starting materials were grinded in a ball mill (Pulverisette 23, Fritsch) or manually with a mortar and pestle. For LAG experiments, the value of volume of solvent/sample weight was fixed at 0.15 μl/mg. Typically, ball milling was performed at 40 Hz for 20 min using a 10 ml stainless steel jar and a 15-mm grinding balls. For manual grinding experiment, a reaction time of 30 min was used. Generally, each grinding experiment were performed in duplicate or triplicate. It will be mentioned if a mechanochemical experiment using other grinding parameters. Powder X-ray diffraction (powder XRD) 3

4 Powder XRD experiments were performed on a Bruker D8 Advance X-ray powder diffractometer (Bruker AXS, Karlsruhe, Germany) equipped with a LynxEye detector (Cu Kα radiation). The tube current and voltage of the generator were set to 40 ma and 40 kv, respectively. The data were collected over the 2θ range from 3 to 40 scanning with a step size of at ambient temperature. Single crystal X-ray diffraction (single crystal XRD) Single crystal XRD data of THP-AH11 were collected using an Xcalibur, Atlas, Gemini diffractometer (Agilent, Santa Clara, California) with graphite monochromated Cu Kα radiation (λ = Å) at 223 K. The crystal structure was solved and refined using the SHELXL program. 3 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms associated with carbon atoms were fixed in geometrically constrained positions. The active hydrogen atoms on the O/N H groups were located from the difference Fourier map. 4

5 Figure S1 Simulated powder XRD pattern of THP-AH12, and experimental pattern of THP-AH12 obtained via neat grinding manually. Figure S2 Simulated powder XRD patterns of THP form II, THP-AH12, and typical experimental pattern of co-grinding products of 1:1 THP II and AH I using a mortar and pestle. 5

6 (e) (d) Figure S3 Simulated powder XRD patterns of THP-AH11 and THP-AH12. Experimental XRD patterns of ethanol-assisted grinding products of 1:1 THP II and AH I in a ball milling experiment using different reaction times: 5 min, 10 min (d), and 20 min (e). Figure S4 Simulated powder XRD patterns of THP-AH11 and THP-AH12. Experimental powder XRD pattern for the ethanol-assisted co-grinding product of THP-AH12, THP-AH11, and THP form II using a ball mill. 6

7 (e) (d) Figure S5 Simulated powder XRD patterns of THP-AH11 and THP-AH12. Experimental patterns of ethanol-assisted grinding products of 1:2 THP II and AH I in a ball mill using different reaction times: 30 s, 5 min (d), and 20 min (e). (d) Figure S6 The simulated (a, c) and experimental (b, d) powder XRD patterns of AH form I (a, b) and form II (c, d). 7

8 (f) (e) (d) Figure S7 Simulated powder XRD patterns of THP form II, AH form II, THP-AH11, and THP-AH12 (d). Experimental patterns of ethanol-assisted grinding products of 1:1 THP II and AH II in a ball mill using different reaction times: 5 min (e), 20 min (f). References 1 S. P. Velaga, V. R. Vangala, S. Basavoju, D. Boström, Chem. Commun, 2010, 46, L. Seton, D. Khamar, I. J. Bradshaw and G. A. Hutcheon, Cryst. Growth Des., 2010, 10, G. M. Sheldrick, Acta Cryst. 2015, C71,