博碩士論文 953204062 詳細資訊




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姓名 侯宏儒(Hung-ju Hou)  查詢紙本館藏   畢業系所 化學工程與材料工程學系
論文名稱 西咪替丁的初始溶劑篩選應用在球形結晶技術來做固體藥劑的精益製造
(Spherical Crystallization for Lean Solid-Dose Manufacturing by Initial Solvent Screening: The Study of Cimetidine)
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摘要(中) 藥物的研究與發展是一個很費時與昂貴的過程。平均來說,一個新藥物從在實驗室研發到真正上市大約需要500到880億美元,而且整個過程需要約15年。在本論文中,三個重要的研究方向被用來增進整個藥物研發的效率。首先,我們建立了一個有關西咪替丁(cimetidine)結晶的資料庫。利用23種有機溶劑篩選的方式,有關西咪替丁溶解度(solubility)、多晶形(polymorph)、晶體外貌(crystal habit)、以及結晶度(crystallinity)的資料被完整收集。一種概略但簡單方便且只需要少量樣品的篩選方法也將在本論文中介紹給大家。第二,我們利用球形結晶方法代替傳統濕式造粒,減少固體藥劑製成步驟。此法可被用來增加藥物的流動性並減少固體藥劑製成的時間與花費。第三部分,利用多晶形表(Form Space),來找出有可能形成球形結晶的組合。由於一般的球形結晶選取溶劑的方法是未知,所以本論文利用有系統並方便的方法找出有可能的組合。因為西咪替丁具已經有很多的研究文獻,我們選擇它當作我們的活性藥物成分(active pharmaceutical ingredient, API)。但是本論文中的研究方法,也可以用在其他的活性藥物成分、候選藥物或是簡單的有機分子上。
摘要(英) Drug discovery and development process is a long and expensive process. The average cost of a new drug from laboratory to market is about US$500 to US$880 million and it takes ten to fifteen years to complete all the processes. Three important studies in this thesis were performed to improve the efficiency of the discovery and development process. Firstly, a useful engineering data bank of solubility, polymorphism, crystal habits and crystallinity by solvent screening for cimetidine would be established and a robust, miniature solvent screening method would be introduced. Secondly, a spherical crystallization technique replaces the traditional wet granulation for lean solid-dose manufacturing. This technique could be used to increase the flowability of active pharmaceutical ingredient (API) and save the money and time of solid-dose manufacturing. Thirdly, we used the Form Space to find the possible three-solvent combinations for spherical crystallization. Choosing the possible three-solvent combinations method for spherical crystallization is not clear. In this thesis, the Form Space was used to make the search of the possible three-solvent combinations more systematic and easy. Cimetidine was chosen as the active pharmaceutical ingredient because of its abundance in literatures. But the investigation methods in this thesis could also be applied to some other APIs or drug candidates or simple organic materials.
關鍵字(中) ★ 多晶形表
★ 初始溶劑篩選
★ 晶貌
★ 多晶形
★ 結晶度
★ 溶解度
★ 球形結晶
★ 西咪替丁
關鍵字(英) ★ form space
★ initial solvent screening
★ polymorph
★ solubility
★ crystal habit
★ spherical crystallization
★ cimetidine
★ crystallinity
論文目次 Table of Contents
摘要..............................................................I
ABSTRACT..........................................................II
ACKNOWLEDGMENTS ..................................................III
LIST OF TABLES ...................................................VIII
LIST OF FIGURES ..................................................IX
CHAPTER 1 EXECUTIVE SUMMARY.................................1
1.1 INTRODUCTION..............................................1
1.2 BRIEF INTRODUCTION OF CIMETIDINE..........................5
1.3 CONCEPTUAL FRAMEWORK......................................6
1.4 REFERENCES................................................8
CHAPTER 2 ANALYTICAL INSTRUMENTS............................12
2.1 INTRODUCTION..............................................12
2.2 MICROSCOPIC METHODS.......................................14
2.1.1 Optical Microscopy (OM)...................................14
2.1.2 Low Vacuum Scanning Electron Microscopy (LVSEM)...........16
2.1 SPECTROSCOPIC IDENTIFICATION..............................19
2.1.1 Fourier Transform Infrared (FT-IR) Spectroscopy...........19
2.2 CRYSTALLOGRAPHY...........................................21
2.2.1 Powder X-ray Diffractometry (PXRD)........................21
2.3 THERMAL ANALYSIS..........................................24
2.3.1 Differential scanning calorimetry (DSC)...................24
2.4 CONCLUSIONS...............................................27
2.5 REFERENCES................................................28
CHAPTER 3 SOLUBILITY, CRYSTAL HABITS, POLYMORPHISM, AND
CRYSTALLINITY OF CIMETIDINE BY INITIAL SOLVENT SCREENING..........33
3.1 INTRODUCTION..............................................33
3.1.1 Solubility................................................35
3.1.2 Crystal habit.............................................36
3.1.3 Polymorphism..............................................37
3.1.4 Crystallinity.............................................39
3.2 MATERIALS.................................................41
3.2.1 Cimetidine................................................41
3.2.2 Solvents..................................................45
3.3 EXPERIMENTS METHODS.......................................49
3.3.1 Solubility test...........................................49
3.4 INSTRUMENTATION...........................................51
3.4.1 Optical Microscopy (OM)...................................51
3.4.2 Fourier Transform Infrared (FT-IR) Spectroscopy...........51
3.4.3 Differential Scanning Calorimetry (DSC)...................51
3.4.4 Powder X-ray Diffractometry (PXRD)........................52
3.5 RESULTS AND DISCUSSION....................................53
3.5.1 Solubility................................................53
3.5.2 Crystal Habits............................................61
3.5.3 Polymorphism..............................................64
3.5.4 Crystallinity.............................................68
3.6 CONCLUSIONS...............................................70
3.7 REFERENCES................................................71
CHAPTER 4 SPHERICAL CRYSTALLIZATION OF CIMETIDINE...........80
4.1 INTRODUCTION..............................................80
4.2 MATERIALS.................................................89
4.2.1 Drug......................................................89
4.2.2 Solvents..................................................90
4.3 EXPERIMENTAL METHODS......................................93
4.4 INSTRUMENTATION...........................................97
4.4.1 Fourier Transform Infrared (FT-IR) Spectroscopy...........97
4.4.2 Powder X-ray Diffractometry (PXRD)........................97
4.4.3 Low Vacuum Scanning Electron Microscopy (LVSEM)...........98
4.4.4 Orbital shaker............................................98
4.4.5 Digital Camera............................................98
4.5 RESULTS AND DISCUSSION....................................99
4.5.1 The results of combinations of spherical crystallization..99
4.5.2 The shape and form of the spherical agglomerates..........104
4.5.3 The micromeritic and mechanical properties of agglomerated
crystals..................................................107
4.5.4 SEM photomicrographs of spherical surface and inside......107
4.6 CONCLUSION................................................110
4.7 REFERENCES................................................111
CHAPTER 5 CONCLUSIONS AND FUTURE WORK.......................118
5.1 CONCLUSIONS...............................................118
5.2 FUTURE WORK...............................................119
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指導教授 李度(Tu Lee) 審核日期 2008-7-4
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