金剛烷胺與金剛烷胺鹽酸鹽製程的研究與開發｜國立中央大學博碩士論文系統

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研究生：	吳紹暘 Shao-Yang Wu
論文名稱：	金剛烷胺與金剛烷胺鹽酸鹽製程的研究與開發 Process Research and Development of Amantadine and Amantadine Hydrochloride.
指導教授：	李度 Tu Lee
口試委員:
學位類別：	碩士 Master
系所名稱：	工學院 - 化學工程與材料工程學系 Department of Chemical & Materials Engineering
論文出版年：	2017
畢業學年度：	105
語文別：	中文
論文頁數：	120
中文關鍵詞：	製程開發
外文關鍵詞：	Process Research and Development
相關次數：	點閱：10 下載：0
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煤炭是一種廉價且易於取得的能源，在地球上的儲量豐富，但其缺點是無論用於發電還是焦化，煤都會產生大量的二氧化碳，為了使燃燒煤炭這個過程獲得更多的附加價值，我們將燃燒煤炭與高利潤藥物金剛烷胺結合，並進一步將金剛烷胺製成金剛烷胺鹽酸鹽，以改善金剛烷胺溶解度不佳的問題。本研究共分為兩個部分，首先透過初步的溶劑篩選以及再結晶來了解金剛烷胺與金剛烷胺鹽酸鹽的物化性質，發現金剛烷胺透過在不同溶劑中再結晶後具有層狀結構，此外，金剛烷胺鹽酸鹽則被發現在苯甲醇中再結晶後，會形成2:1的金剛烷胺鹽酸鹽－苯甲醇的溶劑化物。在製藥產業中，溶劑化物的形成是不被期望的，因為它影響活性藥物成分(API)的物化性質，如密度、熔點和溶解速率，因此，避免在反應過程中使用會形成溶劑化物的溶劑是很重要的。第二部分是金剛烷胺與金剛烷胺鹽酸鹽的合成，依據文獻，將反應物乙醯胺金剛烷水解來合成金剛烷胺，並利用水蒸氣蒸餾將金剛烷胺分離，從1H NMR的分析結果找出水解的最佳反應條件。經過PXRD的鑑定，發現合成的金剛烷胺具有部分的層狀結構，並透過熱分析儀器說明層狀結構對金剛烷胺帶來的影響。鹽酸金剛烷胺的合成過程原本需要進行蒸餾、添加反溶劑以及冷卻，這些步驟繁複且耗能。為了改善這些缺點，我們開發了一個簡單、強大且節能的製程，藉由在室溫下進行漿料結晶來製備金剛烷胺鹽酸鹽，並透過不同的分析儀器證明，不論是市售或是我們所合成的金剛烷胺，鹽酸金剛烷胺都可以成功地被合成。而在反應結束後，透過控制溫度的方式對鹽酸金剛烷胺的粒徑分布(PSD)進行控制，使其更有利於工業化的量產。

Coal is a cheap, easy-to-get energy, and abundant on Earth. Its disadvantage is the production of lots of carbon dioxide when it is used to generate electricity or coking. To get more added values during coal-coking, a high profit pharmaceutical product amantadine is combined, which is usually made to hydrochloride salt－amantadine hydrochloride, to overcome the poor solubility problem of amantadine. This study was divided into two parts. First, initial solvent screening and recrystallization were performed to understand the physicochemical properties of amantadine and amantadine hydrochloride crystals. It was found that amantadine having a lamellar assembly after recrystallization. In addition, the 2:1 amantadine hydrochloride．benzyl alcohol solvate was also discovered by re-crystallization of amantadine hydrochloride in benzyl alcohol. In the pharmaceutical industry, the formation of solvate was unpreferable and had many implications, because it affected the original physicochemical properties of the active pharmaceutical ingredient (API), such as density, melting point and dissolution rate. According to the original synthetic method, amantadine was synthesized by hydrolysis of 1-acetamidoadamantane, and was separated by steam distillation. The optimum reaction conditions for hydrolysis were determined by the results of 1H NMR analysis. The synthesized amantadine had partial lamellar assemblies as indicated by the PXRD pattern, and the effect of lamellar assembly on the amantadine was demonstrated by thermal analysis. The synthetic process of amantadine hydrochloride originally required the use of distillation, anti-solvent addition and cooling. Those steps were complicated and energy intensive. To overcome those shortcomings, a robust, intensified and energy-efficient process was developed by using slurry crystallization at room temperature for 30 min, and amantadine hydrochloride could be synthesized successfully as evidenced by NMR, PXRD, TGA and DSC regardless of the source materials used for amantadine. Furthermore, after the completion of the reaction, the particle size distribution of amantadine hydrochloride could be well controlled by the temperature cycles, which was more beneficial to industrial production.

Chapter 1    Introduction    1
1    Research Motives and Backgrounds    1
2    Salt Formation    3
3    Brief Introduction of Amantadine and Amantadine Hydrochloride    6
4    Conceptual Framework    12
5    References    14
Chapter 2    Experimental Materials and Methods    19
1    Materials    19
1.1    Chemicals    19
1.2    Solvents    19
2    Experimental Procedures    22
2.1    Initial Solvent Screening    22
2.2    Solubility Test    23
2.3    Preparation of Amantadine Having a Lamellar Assembly by Evaporative Crystallization    23
2.4    Preparation of 2:1 Amantadine Hydrochloride．Benzyl Alcohol Solvate by Cooling Crystallization    24
2.5    Preparation of Single Crystal for Amantadine Hydrochloride by Cooling Crystallization    24
2.6    Chemical Synthesis of Amantadine    25
2.7    Chemical Synthesis of Amantadine Hydrochloride    27
2.7.1    Reference Method    27
2.7.2    Intensified Method    28
3    Analytical Measurements    30
3.1    Fourier Transform Infrared (FT-IR) Spectroscopy    30
3.2    Nuclear Magnetic Resonance (NMR)    30
3.3    Differential Scanning Calorimetry (DSC)    30
3.4    Thermal Gravimetric Analysis (TGA)    31
3.5    Powder X-ray Diffraction (PXRD)    31
3.6    Single Crystal X-ray Diffraction (SXD)    31
3.7    Optical Microscopy (OM)    32
4    References    33
Chapter 3    Results and Discussion    34
1    Re-crystallization of Amantadine and Amantadine Hydrochloride    34
1.1    Initial Solvent Screening for Amantadine and Amantadine Hydrochloride    34
1.2    Preparation for Lamellar Assembly of Amantadine by Evaporative Crystallization    38
1.3    Preparation for Amantadine Hydrochloride．Benzyl Alcohol Solvate by Cooling Crystallization    40
2    Chemical Synthesis of Amantadine    44
3    Chemical Synthesis of Amantadine Hydrochloride and Particle Size Distribution Control    55
3.1    Chemical Synthesis of Amantadine Hydrochloride    55
3.2    Particle Size Distribution Control    63
4    Overall Mass Balance    65
5    References    66
Chapter 4    Conclusions and Future Works    69
1    Conclusions    69
2    Future Works    71
3    Reference    72
Appendix I Log sheet for Process of Synthesis of Amantadine    73
Appendix II Log sheet for Process of Synthesis of Amantadine Hydrochloride    87
References    104


                                

Chapter 1
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Chapter 2
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.
Lee, T.; Su, Y. C.; Hou, H. J.; Hsieh, H. Y. Initial Solvent Screening of Carbamazepine, Cimetidine, and Phenylbutazone: Part 1 of 2. Pharm. Technol. 2009, 33 (5), 62-72.
He, J. X.; Wang H. B.; Zhou, H. Y. Synthesis of Amantadine Hydrochloride. Chinese J. Pharm. 2013, 44 (1), 1-3.
Kim, S.; Wei, C.; Kiang, S. Crystallization Process Development of an Active Pharmaceutical Ingredient and Particle Engineering via the Use of Ultrasonics and Temperature Cycling. Org. Process Res. Dev. 2003, 7 (6), 997-1001.

Chapter 3
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.
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Lee, T.; Lee, Y.; Lee, H. L.; Syue, Y. R.; Chiu, Y. H.; Liou, J. Y.; Sun, Y. S. Bio-Inspired Phase Change Materials Designed for High Specific Heat of Solid Phase. Thermochim. Acta. 2014, 591, 61-67.
Bhattacharya, S.; Saha, B. K. Polymorphism Through Desolvation of the Solvates of a van der Waals Host. Cryst. Growth Des. 2013, 13 (2), 606-613.
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Chapter 4
Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P. Crystal Engineering Approach to Forming Cocrystals of Amine Hydrochlorides with Organic Acids. Molecular Complexes of Fluoxetine Hydrochloride with Benzoic, Succinic, and Fumaric Acids. J. Am. Chem. Soc. 2004, 126 (41), 13335-13342.
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Sanphui, P.; Mishra, M. K.; Ramamurty, U.; Desiraju, G. R. Tuning Mechanical Properties of Pharmaceutical Crystals with Multicomponent Crystals: Voriconazole as a Case Study. Mol. Pharmacol. 2015, 12 (3), 889-897.
Lee, T.; Chen, J. W.; Lee, H. L.; Lin, T. Y.; Tsai, Y. C.; Cheng, S.L.; Lee, S. W.; Hu, J. C.; Chen, L. T. Stabilization and Spheroidization of Ammonium Nitrate: Co-Crystallization with Crown Ethers and Spherical Crystallization by Solvent Screening. Chem. Eng. J. 2013, 225 (1), 809-817.
Parmar, V. K.; Shah, S. A. Hydrochloride Salt Co-Crystals: Preparation, Characterization and Physicochemical Studies. Pharm. Dev. Technol. 2013, 18(2), 443-453.

Appendix
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