論文目次 |
Table of Contents
摘要 i
Abstract ii
Acknowledgement iv
Table of Contents v
List of Figures viii
List of Tables xiii
List of Schemes xiv
Chapter 1 Introduction 1
1.1 Micromixing, Mesomixing, and Macromixing 1
1.2 Mixing in Reaction Crystallization 3
1.3 Co-crystals 4
1.4 HBz, NaBz, and 1:1 and 2:1 Co-crystals of HBz-NaBz 5
1.5 Framework 9
1.6 References 11
Chapter 2 Experimental Materials and Methods 15
2.1 Materials 15
2.1.1 Chemical 15
2.1.2 Solvent 15
2.2 Experimental Procedures 15
2.2.1 Synthesizing 2:1 Co-crystals of Benzoic Acid-Sodium Benzoate (HBz-NaBz) by Cooling Method 15
2.2.2 The Study of Synthesizing Co-crystals of Benzoic Acid-Sodium Benzoate (HBz-NaBz) by adding Hydrochloric Acid 17
2.2.3 The Study of Different Scales of Mixing Effect to Co-crystals of HBz-NaBz by Feeing Hydrochloric Acid in the Stirred Vessel 20
2.2.4 Extreme Mixing Conditions for the HBz-NaBz Co-crystals Formation 23
2.2.5 Wet Sieve Analysis Method 25
2.3 Analytical Measurements 26
2.3.1 Powder X-ray Diffraction (PXRD) 26
2.3.2 Fourier Transform Infrared (FTIR) Spectroscopy 27
2.3.3 Thermal Gravimetric Analysis (TGA) 28
2.3.4 Optical Microscopy (OM) 28
2.4 References 30
Chapter 3 Results and Discussion 31
3.1 Use Tests 31
3.2 Synthesizing Co-crystals by Different Molar Ratios of NaBz to HCl 36
3.3 Different Scales of Mixing Effect on the HBz-NaBz Co-crystals 41
3.3.1 The Study of Different Scales of Mixing Effect to the HBz-NaBz Co-crystals According to Table 2.2 42
3.3.2 Extreme Mixing Conditions for the HBz-NaBz Co-crystals Formation According to Table 2.3 58
3.3.3 Particle Size Distribution 65
3.4 References 69
Chapter 4 Conclusions and Future Works 71
4.1 Conclusions 71
4.2 Future Works 73
4.3 References 74
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List of Figures
Figure 1.1 Crystalline form of co-crystal. 4
Figure 1.2 Crystal structure of NaBz (a) Form I, and (b) Form II. 6
Figure 1.3 Crystal structure of 2:1 co-crystals of HBz-NaBz (a) Form A, and (b) Form B. 8
Figure 2.1 The process of synthesizing 2:1 co-crystals of HBz-NaBz. 16
Figure 2.2 The process of synthesizing co-crystals of HBz-NaBz. 17
Figure 2.3 The dimension of propeller and reactor. 20
Figure 2.4 The process of synthesizing co-crystals of HBz-NaBz in the stirred reactor. 22
Figure 2.5 The process of synthesizing HBz-NaBz co-crystals in a stirred reactor. 24
Figure 2.6 Powder X-ray diffraction (PXRD). 26
Figure 2.7 Fourier transform infrared (FT-IR) spectroscopy. 27
Figure 2.8 Thermal gravimetric analyzer (TGA). 28
Figure 2.9 Optical microscopy. 29
Figure 3.1 PXRD Patterns of the purchased (a) NaBz, and (b) HBz, the synthesized (c) 1:1 co-crystals of HBz-NaBz, and (d) 2:1 co-crystals of HBz-NaBz (◆ NaBz,○ 1:1 co-crystals of HBz-NaBz, ● 2:1 co-crystals of HBz-NaBz, and ? HBz).- 31
Figure 3.2 FTIR spectra of the purchased (a) NaBz, (b) HBz, the synthesized (c) 2:1 32
Figure 3.3 TGA scan of NaBz. 33
Figure 3.4 TGA scan of HBz. 33
Figure 3.5 TGA scan of 1:1 co-crytals of HBz-NaBz. 34
Figure 3.6 TGA scan of 2:1 co-crytals of HBz-NaBz. 34
Figure 3.7 TGA scans of (a) Experiment No.1, (b) Experiment No. 2, (c) Experiment No. 3, (d) Experiment No. 4, (e) Experiment No. 5, and (f) Experiment No. 6 based on Table 2.1. 37
Figure 3.8 PXRD patterns of (a) Experiment No.1, (b) Experiment No. 2, (c) Experiment No. 3, (d) Experiment No. 4, (e) Experiment No. 5, and (f) Experiment No. 6 based on Table 2.1 (? HBz, ○ 1:1 co-crystals of HBz-NaBz, and ● 2:1 co-crystals of HBz-NaBz). 37
Figure 3.9 OM images of (a) Experiment No.1, (b) Experiment No. 2, (c) Experiment No. 3, (d) Experiment No. 4, (e) Experiment No. 5, and (f) Experiment No. 6 based on Table 2.1 (scale bar = 200 μm). 38
Figure 3.10 TGA scans of the samples harvested in Experiment No. 7 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min. 43
Figure 3.11 PXRD patterns of the samples harvested in Experiment No. 7 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (? HBz, ○ 1:1 co-crystals of HBz-NaBz, and ● 2:1 co-crystals of HBz-NaBz). 43
Figure 3.12 OM images of the samples harvested in Experiment No. 7 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (scale bar = 200 μm). 44
Figure 3.13 TGA scans of the samples harvested in Experiment No. 8 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min. 46
Figure 3.14 PXRD patterns of the samples harvested in Experiment No. 8 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (? HBz, ○ 1:1 co-crystals of HBz-NaBz, and ● 2:1 co-crystals of HBz-NaBz). 46
Figure 3.15 OM images of the samples harvested in Experiment No. 8 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (scale bar = 200 μm). 47
Figure 3.16 TGA scans of the samples harvested in Experiment No. 9 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min. 49
Figure 3.17 PXRD patterns of the samples harvested in Experiment No. 9 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (? HBz, ○ 1:1 co-crystals of HBz-NaBz, and ● 2:1 co-crystals of HBz-NaBz). 50
Figure 3.18 OM images of the samples harvested in Experiment No. 9 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (scale bar = 200 μm). 51
Figure 3.19 TGA scans of the samples harvested in Experiment No. 10 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min. 53
Figure 3.20 PXRD patterns of the samples harvested in Experiment No. 10 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (? HBz, ○ 1:1 co-crystals of HBz-NaBz, and ● 2:1 co-crystals of HBz-NaBz). 53
Figure 3.21 OM images of the samples harvested in Experiment No. 10 based on Table 2.2 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (scale bar = 200 μm). 54
Figure 3.22 The mixing effect on the evolution of co-crystals of HBz-NaBz. 57
Figure 3.23 TGA scans of the samples harvested in Experiment No. 11 based on Table 2.3 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min. 59
Figure 3.24 PXRD patterns of the samples harvested in Experiment No. 11 based on Table 2.3 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (? HBz, ○ 1:1 co-crystals of HBz-NaBz, and ● 2:1 co-crystals of HBz-NaBz). 59
Figure 3.25 OM images of the samples harvested in Experiment No. 11 based on Table 2.3 at (a) 1 min, (b) 3 min, (c) 5 min, (d) 10 min, (e) 20 min, (f) 30 min, and (g) 240 min (scale bar = 200 μm). 60
Figure 3.26 TGA scans of the samples harvested in Experiment No. 12 based on Table 2.3 at (a) 10 min, (b) 20 min, (c) 30 min, and (d) 240 min. 62
Figure 3.27 PXRD patterns of the samples harvested in Experiment No. 12 based on Table 2.3 at (a) 10 min, (b) 20 min, (c) 30 min, and (d) 240 min (? HBz, ○ 1:1 co-crystals of HBz-NaBz, and ● 2:1 co-crystals of HBz-NaBz). 62
Figure 3.28 OM images of the samples harvested in Experiment No. 12 based on Table 2.3 at (a) 10 min, (b) 20 min, (c) 30 min, and (d) 240 min (scale bar = 200 μm). 63
Figure 3.29 The pathway of crystal formation based on Experiment No. 12. 64
Figure 3.30 The crystal size distribution on each sieve plate of co-crystals of HBz-NaBz produced from (a) Experiment No. 7, (b) Experiment No. 8, (c) Experiment No. 9, (d) Experiment No. 10 based on Table 2.2 at 240 min. 66
Figure 3.31 The dissolution rate and re-crystallization rate based on film theory at (a) low flow rate, and (b) high flow rate. 67
Figure 4.1 The flow diagram of scale up of reactor. 73
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List of Tables
Table 1.1 The crystallographic data for Form I and Form II of NaBz. 6
Table 1.2 The crystallographic data for Form A and Form B of 2:1 co-crystals of HBz-NaBz. 8
Table 2.1 Experimental conditions for the formation of co-crystals of HBz-NaBz in different molar ratios of NaBz to HCl. 19
Table 2.2 Experimental conditions for the formation of co-crystals of HBz-NaBz in the stirred reactor under different agitation rates and feeding rates. 22
Table 2.3 Two experimental conditions for the formation of HBz-NaBz co-crystals. 24
Table 3.1 The calculation of weight (%) of HBz and NaBz in the co-crystals system. 35
Table 3.2 The results of the synthesized co-crystals by different molar ratios of NaBz to HCl. 40
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List of Schemes
Scheme 2.1 The pathway of reaction of sodium benzoate with hydrochloric acid. 17
Scheme 2.2 The chemistry of synthesizing co-crystals of HBz-NaBz. 20 |
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