Crystal Size Enlargement in Reactive Crystallization for Processing and Powder Handling: The Study of Dicumarol

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張鉯雯(Yi-Wen Chang) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

(Crystal Size Enlargement in Reactive Crystallization for Processing and Powder Handling: The Study of Dicumarol)

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摘要(中)

從製程的角度是不希望反應結晶中收穫尺寸為 0.1 至 10 μm細小的固體晶粒，這可能會導致下游的單元操作，如過濾、洗滌和乾燥出現問題。此外，其他物理特性，如堆積密度、粉末流動性、團聚和晶體尺寸分佈(CSD)，可能會導致儲存、配製和運輸困難。本研究以雙香豆素為模型藥物，由4-羥基香豆素與甲醛在水中縮合反應合成。由於雙香豆素極不溶於水，在反應結晶過程中，雙香豆素晶體在1 分鐘內迅速析出，且晶體尺寸小於5 μm，導致在過濾和乾燥過程中形成硬塊。因此，本研究的目的是增加雙香豆素在反應結晶中的晶體尺寸，並進一步改善粉末特性。首先，通過對24種溶劑的初步溶劑篩選，將N,N-二甲基乙醯胺(DMAc)代替水作為反應溶劑提高雙香豆素的溶解度，以降低成核速率，提供了較寬的操作範圍，從而產生大尺寸的雙香豆素晶體。本論文討論了雙香豆素合成後晶體通過冷卻而緩慢結晶，結果成功製備了接近100 μm的雙香豆素晶體。此外，藉著改變反應結晶中甲醛溶液的添加方式，將過飽和度控制在較低的值，避免快速成核，而有利於晶體生長。在實驗過程中對反應溶液進行取樣，從光學顯微鏡(OM)觀察晶體尺寸的演變，深入研究其動力學和比較最終的實驗結果，成功地將雙香豆素的晶體尺寸提高到約200 μm，且產率高達85.3%。HPLC純度測定為103.1%。卡爾指數和休止角的測量，分別為16.4±1.6% 和37.0±0.5°，顯示出粉末特性有顯著改善。所有固體樣品皆通過傅立葉轉換紅外線光譜儀(FT-IR)和粉末X射線衍射儀(PXRD)的檢查，以確定最終產品的固態特性。

摘要(英)

Fine solid particles are often harvested in reactive crystallization. From the perspective of process engineering, fine crystals with sizes of 0.1 to 10 μm are undesirable, for they can cause problems in downstream unit operations, such as filtration, washing and drying. In addition, other physical properties, such as bulk density, powder flowability, agglomeration, and crystal size distribution (CSD), may cause difficulties in storage, formulation, and transportation. Dicumarol was used as a model drug in this research, and synthesized by condensation reaction of 4-hydroxycoumarin with formaldehyde originally in water. Since dicumarol is extremely insoluble in water, dicumarol crystals would be rapidly precipitated in 1 min during the course of reactive crystallization, and the resulting crystal size was less than 5 μm. Very fine dicumarol crystals led to the formation of hard lumps during filtration and drying. Therefore, the aim of this research is to increase the crystal size of dicumarol in reactive crystallization, and to further improve powder properties. First, through an initial solvent screening among 24 solvents, N,N-dimethylacetamide (DMAc) was identified to be suitable for substituting for water to improve the solubility of dicumarol, which provided a relatively wide operating window to reduce the nucleation rate, and thereby, produced large-sized dicumarol crystals. In this thesis, it was discussed that the crystals were slowly crystallized by cooling after the synthesis of dicumarol, and the result has successfully produced dicumarol crystals near 100 μm. In addition, the degree of supersaturation could be controlled at a lower value by changing the addition mode of the formaldehyde aqueous solution in reactive crystallization. Fast nucleation could be avoided thereby favoring crystal growth. The reaction solution was sampled during the experiment, the evolution of crystal habit was observed by optical microscopy (OM), and its kinetic process was thoroughly studied and compared. The final experimental results have successfully increased the crystal size of dicumarol to about 200 μm, and the yield was up to 85.3%. The HPLC assay was 103.1%. The powder properties, including Carr’s index and angle of repose, were measured, and our best case showed the much improved values of 16.4±1.6% and 37.0±0.5°, respectively. All sample solids were characterized by Fourier transform infrared spectroscopy (FT-IR) and powder X-ray diffraction (PXRD) to identify the chemical and crystal properties of the final products.

關鍵字(中)

★ 反應結晶
★ 晶體尺寸
★ 雙香豆素

關鍵字(英)

★ Reactive Crystallization
★ Crystal Size
★ Dicumarol

論文目次

摘要 i
Abstract ii
Acknowledgment iv
Table of Contents vi
List of Figures ix
List of Tables xv
List of Schemes xvi
Chapter 1 Introduction 1
1.1 Reactive Crystallization in Pharmaceutical Industry 1
1.2 Importance of Particle Size in APIs Manufacturing 4
1.3 Particle Size Enlargement 7
1.4 Fundamentals of Crystallization 12
1.5 Brief Introduction of Dicumarol 15
1.6 Conceptual Framework 19
1.7 References 21
Chapter 2 Experimental Materials and Method 30
2.1 Materials 30
2.1.1 Chemicals 30
2.1.2 Solvents 31
2.2 Experimental Procedures 33
2.2.1 Experimental Framework 33
2.2.2 Initial Solvent Screening 34
2.2.3 Experimental Solubility Measurements 36
2.2.4 Synthesis of Dicumarol by the Literature Method 38
2.2.5 Recrystallization of Purchased Dicumarol 40
2.2.6 Experimental Conditions for Chemical Reaction 41
2.2.7 Cooling Crystallization After Synthesis of Dicumarol 43
2.2.8 Synthesis of Dicumarol by Reactive Crystallization 46
2.2.9 Sieve Analysis 49
2.2.10 Assay Procedure 51
2.2.11 Carr’s Index 52
2.2.12 Angle of Repose 53
2.3 Analytical Measurements 54
2.3.1 Polarized Optical Microscopy (POM) 54
2.3.2 Fourier Transform Infrared (FT-IR) Spectroscopy 55
2.3.3 Powder X-Ray Diffraction (PXRD) 56
2.3.4 High Performance Liquid Chromatography (HPLC) 57
2.4 References 59
Chapter 3 Results and Discussion 61
3.1 Solvent Selection 61
3.2 Solubility Curve 65
3.3 Solid-State Characterizations of Dicumarol 66
3.3.1 Fourier Transform Infrared (FT-IR) Spectroscopy 66
3.3.2 Powder X-Ray Diffraction (PXRD) Patterns 67
3.4 Particle Size Enlargement of Dicumarol in Reactive Crystallization 69
3.4.1 The Literature Method 69
3.4.2 Cooling Crystallization After Synthesis of Dicumarol 74
3.4.3 Reactive Crystallization Method 79
3.5 Powder Flowability 102
3.6 References 104
Chapter 4 Conclusions and Future Works 106
4.1 Conclusions 106
4.2 Future Works 108

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Chapter 2
1. Lee, T.; Kuo, C. S.; Chen, Y. H. Solubility, polymorphism, crystallinity, and crystal habit of acetaminophen and ibuprofen by initial solvent screening. Pharm. Technol. 2006, 30(10), 72-92.
2. Anderson, N. G. Solvent Selection. In Practical Process Research and Development, 2nd ed.; Academic press: New York, 2012; pp. 121-168.
3. Petnapapun, K.; Chavasiri, W.; Sompornpisut, P. Structure-activity relationships of 3,3′-phenylmethylene-bis-4-hydroxycoumarins: selective and potent inhibitors of gram-positive bacteria. Sci. World J. 2013, 178649, 1-11.
4. Lin, P. Y.; Lee, H. L.; Chen, C. W.; Lee, T. Effects of baffle configuration and tank size on spherical agglomerates of dimethyl fumarate in a common stirred tank. Int. J. Pharm. 2015, 495(2), 886-894.
5. Lee, T.; Lin, H. Y.; Lee, H. L. Engineering reaction and crystallization and the impact on filtration, drying, and dissolution behaviors: the study of acetaminophen (paracetamol) by in-process controls. Org. Process Res. Dev. 2013, 17(9), 1168-1178.
6. Lee, T.; Hsu, F. B. A cross-performance relationship between Carr′s index and dissolution rate constant: the study of acetaminophen batches. Drug Dev. Ind. Pharm. 2007, 33(11), 1273-1284.
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Chapter 3
1. Anderson, N. G. Solvent Selection. In Practical Process Research and Development, 1st ed.; Academic press, New York, 2000; pp. 81-112.
2. Croker, D. M.; Kelly, D. M.; Horgan, D. E.; Hodnett, B. K.; Lawrence, S. E.; Moynihan, H. A.; Rasmuson, Å. C. Demonstrating the influence of solvent choice and crystallization conditions on phenacetin crystal habit and particle size distribution. Org. Process Res. Dev. 2015, 19(12), 1826-1836.
3. Mirmehrabi, M.; Rohani, S. An approach to solvent screening for crystallization of polymorphic pharmaceuticals and fine chemicals. J. Pharm. Sci. 2005, 94(7), 1560-1576.
4. Lee, T.; Kuo, C. S.; Chen, Y. H. Solubility, polymorphism, crystallinity, and crystal habit of acetaminophen and ibuprofen by initial solvent screening. Pharm. Technol. 2006, 30(10), 72-92.
5. Yalkowsky, S. H.; He, Y.; Jain, P. Handbook of Aqueous Solubility Data. CRC press, Boca Raton, FL, 2010, p. 1186.
6. Li, J.; Hou, Z.; Chen, G.-H.; Li, F.; Zhou, Y.; Xue, X.-Y.; Li, Z.-P.; Jia, M.; Zhang, Z.-D.; Li, M.-K.; Luo, X.-X. Synthesis, antibacterial activities, and theoretical studies of dicoumarols. Org. Biomol. Chem. 2014, 12(29), 5528-5535.
7. IR Spectrum Table & Chart (https://www.sigmaaldrich.com/technical-documents/articles/biology/ir-spectrum-table.html, accessed on February 21, 2022)
8. Petnapapun, K.; Chavasiri, W.; Sompornpisut, P. Structure-activity relationships of 3,3′-phenylmethylene-bis-4-hydroxycoumarins: selective and potent inhibitors of gram-positive bacteria. Sci. World J. 2013, 178649, 1-11.
9. Beckmann, W. Seeding the desired polymorph: background, possibilities, limitations, and case studies. Org. Process Res. Dev. 2000, 4(5), 372-383.
10. McGinty, J.; Yazdanpanah, N.; Price, C.; Horst, J. H. T.; Sefcik, J. Nucleation and Crystal Growth in Continuous Crystallization. In The Handbook of Continuous Crystallization; Yazdanpanah, N.; Nagy, Z., Eds.; Royal Society of Chemistry: London, U.K, 2020; pp. 1-50.
11. McDonald, M. A.; Salami, H.; Harris, P. R.; Lagerman, C. E.; Yang, X.; Bommarius, A. S.; Grover, M. A.; Rousseau, R. W. Reactive crystallization: a review. React. Chem. Eng. 2021, 6(3), 364-400.
12. Zauner, R.; Jones, A. G. Mixing effects on product particle characteristics from semi-batch crystal precipitation. Chem. Eng. Res. Des. 2000, 78(6), 894-902.
13. Kim, S.; Lotz, B.; Lindrud, M.; Girard, K.; Moore, T.; Nagarajan, K.; Alvarez, M.; Lee, T.; Nikfar, F.; Davidovich, M; Srivastava, S.; Kiang, S. Control of the particle properties of a drug substance by crystallization engineering and the effect on drug product formulation. Org. Process Res. Dev. 2005, 9(6), 894-901.
14. Lumay, G.; Boschini, F.; Traina, K.; Bontempi, S.; Remy, J. C.; Cloots, R.; Vandewalle, N. Measuring the flowing properties of powders and grains. Powder Technol. 2012, 224, 19-27.

指導教授

李度(Tu Lee)

審核日期

2022-7-19

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