The Impact of Reaction Crystallization Paths on Filtration, Drying, and Dissolution Behavior for Acetaminophen via In-Process Controls

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林宏祐(Hong-Yu Lin) 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

(The Impact of Reaction Crystallization Paths on Filtration, Drying, and Dissolution Behavior for Acetaminophen via In-Process Controls)

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摘要(中)

本篇主要之研究目的，在於將製程中各不同單元操作間所需要考慮的因素，經通盤整合與全方位考量後優化整個製程，以期能將設備之效率，提升到最高效能，並做出符合最高標準的成品。
有關本研究反應部分，產物對乙醯氨基酚，於此研究中是利用醋酸酐將對氨基苯酚乙醯化後得到。於設定的實驗條件下，此反應的平均轉化率能達到86.3% 之多。此外，另將主要之研究分成三個不同的案例來做深入之探討，案例一及案例二之差別，在於冷卻的過程中有無攪拌的差異；至於案例二及案例三的區別則為注入氫氧化鈉作為中和劑的時間點不同。透過以上兩種參數的改變，所得到之固體產物會造成不同的粒徑分布、顆粒團聚程度、同質異像體之生成。從粒徑分布圖上，我們可以得知各案例中篩網孔徑介於500 μm到297 μm間的重量百分比序為二 > 三 > 一。整個反應、結晶、中和的實驗過程中，皆被即時地監控並詳實記錄對乙醯氨基酚在溶液中的濃度、pH值、溫度之改變。從當下溶液中的對乙醯氨基酚濃度與該溫度下的理想飽和溶解度對時間作圖，可得知系統相對提供多少勢能作為成核之驅動力。由圖上可以比較出在三個案例中，案例一具有最大的驅動力，造成前期的結晶過程中產生許多微小的晶核，但不足以形成更巨大的晶粒。
至於其他的單元操作如過濾及乾燥，我們可用濾餅阻力及Krischer曲線公式來達到量化顆粒團聚對操作過程的影響之目的。經由實驗結果顯示：案例一的濾餅阻力最大，案例三次之，最後為案例二；而在Krischer曲線圖上，可以看出案例二的軌跡，明顯比其他兩個案例短小及有規律，代表其顆粒團聚較大使得水分能輕易地由內至外蒸發出去。Mixed suspension, mixed product removal (MSMPR)是一種將過濾、乾燥之後的產物，先過篩而得到的粒徑分布作數據分析之方法，藉由此方法，我們可以計算在結晶過程中此系統的成核速率、長晶速率、團聚速率，提供一個相對值，便於比較各案例的差異。分析的結果能與上述討論相互印證，成核速率大小排列為案例一 > 三 > 二；長晶速率排序為案例二 > 三 > 一；團聚速率則以案例二有較好的表現。另外，Carr’s指數可用來量測各案例間粉末流動性之表現。案例二因具有較佳的團聚效果，使外觀接近球狀而表現出較出色的流變性質。而溶解度測試則是製藥研發過程中最重要的一環，藉由藥物在擬人體環境中的釋放速率實驗得知，案例二的藥物釋放效果最差。最後將整個製程產物作質量平衡計算符合預期中的假設，同時也得出一個重要的結論；雖然產率及純度在三個案例中皆大致相同，但藉由不同的製程方法可以讓產物具有不同的物化特性。
此外，我們在案例三的實驗中，意外地發現對乙醯氨基酚的第二個同質異像體，這是全世界的製藥研究人員都在競相追逐的夢幻同質異像體。從差示掃描量熱儀(DSC)圖上可以看出，由案例三所做出來的樣品，具有第二個同質異像體獨有的熔點，至於在傅立葉轉換紅外線光譜儀(FT-IR)及粉末X射線繞射儀(PXRD)圖上的特徵峰拿來與文獻相比亦十分吻合。
我們期待本相關研究，能提供對乙醯氨基酚及其它原料藥，在製程上所遭遇到之難題有所幫助，並對化工領域能略盡棉薄之力。

摘要(英)

The aim of this thesis is to integrate the different research aspects of acetaminophen from the point of view of chemical and materials engineering to optimize the process. In reaction section, the recipe for acetaminophen is acetylating p-aminophenol with acetic anhydride. However, there are three distinct cases of crystallization routes including different agitational method and the time point of neutralization as the main experiments. The average conversion of three different cases is around 86.3%. Weight percent of solid particles retained on 297 μm sieve are in the order of Case II > Case III > Case I. The concentration profile of acetaminophen, pH values, and temperature throughout the reaction, crystallization, and neutralization are monitored by the in-process controls. When local concentration in the reaction solution was compared with the particular saturated concentration obtained from the solubility curve, the driving force for nucleation could be realized. The driving force in Case I was large causing the generation of many small nuclei but insufficient growth in early crystallization among the three cases. As for the other unit operations of filtration and drying, we used the formula of specific cake resistance and Krischer curve to measure the effect of agglomeration. The specific cake resistance was in the order of Case I > Case III > Case II, respectively, and the short drying curve for the wet cake of Case II indicated that it had more large pores within the agglomerates among the three cases. The mixed suspension, mixed product removal (MSMPR) formalism and particle size distribution were employed to calculate the rates of nucleation, crystal growth and agglomeration during crystallization. The results conformed to our expectation that the nucleation and crystal growth rates were in the order of Case I > Case III > Case II, and Case II > Case III > Case I, respectively. The size-dependent aggregation rate for Cases II was the largest meaning the highest frequency of aggregation. In addition, the Carr’s index and dissolution test were used to qualify the flowability of dry powder and the acetaminophen released rate in the simulated environment of human body, respectively. Among these three cases, Case II gave the best rheological property and relatively the slowest drug release rate. Finally, the overall materials balance revealed that the yields and purities of different cases were almost the same. However, the different crystallization paths could affect the crystal habits causing the total different results in physicochemical properties. Furthermore, in Case III paths, we accidentally discovered acetaminophen Form II which was the visionary form for pharmaceutical workers in the world. The DSC scan of the sample showed a melting peak at around 151oC. Meanwhile, the PXRD pattern and IR spectrum of the sample verified that it was acetaminophen Form II. The detail experimental procedures were discussed in the Appendix. We hope that this thesis can provide a significant influence to the pharmaceutical industry in the related research of acetaminophen and other active pharmaceutical ingredient.

關鍵字(中)

★ 對乙醯氨基酚
★ 結晶工程
★ 反應結晶

關鍵字(英)

論文目次

摘要.....i
Abstract.....iii
Acknowledgement.....v
Table of Contents.....vi
List of Figures.....x
List of Schemes.....xv
List of Tables.....xvi
Chapter 1 Executive Summary.....1
1.1 Introduction to Pharmaceutical Industry.....1
1.2 Brief of Acetaminophen (Paracetamol).....9
1.3 Conceptual Framework.....12
1.4 References.....15
Chapter 2 Analytical Instruments.....27
2.1 Introduction.....27
2.2 Thermal Analysis Methods.....31
2.2.1 Differential Scanning Calorimetry (DSC).....31
2.3 Spectroscopic Methods.....35
2.3.1 Fourier Transform Infrared (FT-IR) Spectroscopy.....35
2.3.2 Ultraviolet and Visible (UV/Vis) Spectrophotometer.....38
2.4 Microscopic Methods.....42
2.4.1 Polarized Optical Microscopy (POM).....42
2.4.2 Low Vacuum Scanning Electron Microscope (LVSEM).....45
2.5 Crystallographic Analysis Method.....48
2.5.1 Powder X-ray Diffractometry (PXRD).....48
2.6 Powder Characteristics.....51
2.6.1 Sieving.....51
2.7 Conclusions.....53
2.8 References.....55
Chapter 3 The Impact of Reaction Crystallization Paths on Filtration, Drying, and Dissolution Behavior for Acetaminophen via In-Process Controls.....59
3.1 Introduction.....59
3.2 Mixed Suspension, Mixed Product Removal (MSMPR).....66
3.3 Materials.....71
3.3.1 Chemicals.....71
3.3.2 Solvents.....71
3.4 Experimental Methods.....72
3.4.1 Solubility Curves.....72
3.4.2 In-Process Controls (IPCs).....72
3.4.3 Filtration.....75
3.4.4 Drying.....75
3.4.5 Dissolution.....75
3.5 Analytical Measurements.....77
3.5.1 Temperature Recorder.....77
3.5.2 pH-indicator Strips.....77
3.5.3 Ultraviolet and Visible Spectrophotometer (UV/Vis).....77
3.5.4 Dry Sieve Analysis.....78
3.5.5 Rheological Study (Carr’s Index).....78
3.5.6 Optical Microscopy.....79
3.5.7 Fourier Transform Infrared (FT-IR) Spectroscopy.....79
3.5.8 Powder X-ray Diffractometry (PXRD).....79
3.5.9 Differential Scanning Calorimetry (DSC).....80
3.5.10 Apparatus.....80
3.6 Results and Discussion.....81
3.7 Conclusions.....104
3.8 References.....106
Chapter 4 Conclusions and Future Work.....112
4.1 The Impact of Reaction Crystallization Paths on Filtration, Drying, and Dissolution Behavior for Acetaminophen via In-Process Controls.....112
4.2 Future Work.....115
4.2.1 Developing Continuous Crystallizer System.....115
4.2.2 Replaced by Different Acid and Base Chemical in Reaction and Neutralization System.....116
4.3 References.....117
Appendices.....118
Appendix A.....119
Appendix B.....139

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98. Peterson, M. L.; Morissette, S. L.; McNulty, C.; Goldsweig, A.; Shaw, P.; LeQuesne, M.; Monagle, J.; Encina, N.; Marchionna, J.; Johnson, A.; Gonzalez-Zugasti, J.; Lemmo, A. V.; Ellis, S. J.; Cima, M. J.; Almarsson, Ö., Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III. J. Am. Chem. Soc. 2002, 124 (37), 10958-10959.
99. Di Martino, P.; Conflant, P.; Drache, M.; Huvenne, J. P.; Guyot-Hermann, A. M., Preparation and physical characterization of forms II and III of paracetamol. J. Therm. Anal. Calorim. 1997, 48 (3), 447-458.
100. Moynihan, H. A.; O’Hare, I. P., Spectroscopic characterisation of the monoclinic and orthorhombic forms of paracetamol. Int. J. Pharm. 2002, 247 (1–2), 179-185.
101. Davenport, K. G.; Hilton, C. B., Process for producing N-acyl-hydroxy aromatic amines. US patent4524217, 1985.
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103. Sander, J. R. G.; Bučar, D.-K.; Henry, R. F.; Baltrusaitis, J.; Zhang, G. G. Z.; MacGillivray, L. R., A red zwitterionic co-crystal of acetaminophen and 2,4-pyridinedicarboxylic acid. J. Pharm. Sci. 2010, 99 (9), 3676-3683.
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105. Uusi-Penttilä, M. S.; Rasmuson, Å. C., Experimental study for agglomeration behaviour of paracetamol in acetone–toluene–water systems. Chem. Eng. Res. Des. 2003, 81 (4), 489-495.
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108. Lee, T.; Hung, S. T.; Kuo, C. S., Polymorph farming of acetaminophen and sulfathiazole on a chip. Pharm. Res. 2006, 23 (11), 2542-2555.
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111. 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.
112. Lee, T.; Hou, H. J.; Hsieh, H. Y.; Su, Y. C.; Wang, Y. W.; Hsu, F. B., The prediction of the dissolution rate constant by mixing rules: The study of acetaminophen batches. Drug Dev. Ind. Pharm. 2008, 34 (5), 522-535.
Chapter 2
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3. Skoog, D. A.; Holler, F. J.; Nieman, T. A., Principle of Instrumental Analysis. 5th Ed.; Brooks/Cole, Canada, 1997; Chapter 31, pp 801-807.
4. Clas, S. D.; Dalton, C. R.; Hancock, B. C., Differential scanning calorimetry:
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6. Skoog, D. A.; Holler, F. J.; Nieman, T. A., Principle of Instrumental Analysis. 5th Ed.; Brooks/Cole, Canada, 1997; Chapter 16, pp 392-396.
7. Skoog, D. A.; Holler, F. J.; Crouch, S. R., Principle of Instrumental Analysis. 6th Ed.; Thomson Higher Education, Belmont; Chapter 17, p 405.
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10. Skoog, D. A.; Holler, F. J.; Nieman, T. A., Principles of Instrumental Analysis, 5th Ed.; Brooks/Cole, Canada, 1997; Chapter 13, pp 300-328.
11. Skoog, D. A.; Holler, F. J.; Crouch, S. R., Principles of Instrumental Analysis. 5th Ed.; Brooks/Cole, Canada, 1997; Chapter 14, pp 329-354.
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25. Miura, H.; Ushio, T.; Nagai, K.; Fujimoto, D; Lepp, Z.; Takahashi, H.; Tamura, R., Crystallization of a desired metastable polymorph by pseudoseeding, crystal structure solution from its powder X-ray diffraction data, and confirmation of polymorphic transition. Cryst. Growth Des. 2003, 3 (6), 959-965.
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Chapter 3
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2. 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.
3. Kadam, S. S.; Vissers, J. A. W.; Forgione, M.; Geertman, R. M.; Daudey, P. J.; Stankiewicz, A. I.; Kramer, H. J. M., Rapid crystallization process development strategy from lab to industrial scale with PAT tools in skid configuration. Org. Process Res. Dev. 2012, 16 (5), 769-780.
4. Peterson, M. L.; Morissette, S. L.; McNulty, C.; Goldsweig, A.; Shaw, P.; LeQuesne, M.; Monagle, J.; Encina, N.; Marchionna, J.; Johnson, A.; Gonzalez-Zugasti, J.; Lemmo, A. V.; Ellis, S. J.; Cima, M. J.; Almarsson, Ö., Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III. J. Am. Chem. Soc. 2002, 124 (37), 10958-10959.
5. Parkin, A.; Parsons, S.; Pulham, C. R., Paracetamol monohydrate at 150 K. Acta Crystallogr. Sect. E: Struct. Rep. Online 2002, 58 (12), 1345-1347.
6. Wang, S.-L.; Lin, S.-Y.; Wei, Y.-S., Transformation of metastable forms of acetaminophen studied by thermal fourier transform infrared (FT-IR) microspectroscopy. Chem. Pharm. Bull. 2002, 50 (2), 153-156.
7. Davenport, K. G.; Hilton, C. B., Process for producing N-acyl-hydroxy aromatic amines. US patent 4524217, 1985.
8. Venneri, F., Fast, high-efficiency quantitative synthesis of paracetamol. Euro patent 2266949, 2010.
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11. Ålander, E. M.; Uusi-Penttilä, M. S.; Rasmuson, Å. C., Agglomeration of paracetamol during crystallization in pure and mixed solvents. Ind. Eng. Chem. Res. 2003, 43 (2), 629-637.
12. Lee, T.; Su, Y. C.; Hou, H. J.; Hsieh, H. Y., Spherical crystallization for lean solid-dose manufacturing (Part I). Pharm. Technol. 2010, 34 (3), 72-75.
13. Lee, T.; Su, Y. C.; Hou, H. J.; Hsieh, H. Y., Spherical crystallization for lean solid-dose manufacturing (Part II). Pharm. Technol. 2010, 34 (4), 88-103.
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15. Alvarez, A. J.; Myerson, A. S., Continuous plug flow crystallization of pharmaceutical compounds. Cryst. Growth Des. 2010, 10 (5), 2219-2228.
16. Méndez del Río, J. R.; Rousseau, R. W., Batch and tubular-batch crystallization of paracetamol: crystal size distribution and polymorph formation. Cryst. Growth Des. 2006, 6 (6), 1407-1414.
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18. MacLeod, C. S.; Muller, F. L., On the fracture of pharmaceutical needle-shaped crystals during pressure filtration: case studies and mechanistic understanding. Org. Process Res. Dev. 2012, 16 (3), 425-434.
19. Burgbacher, J.; Wiss, J., Industrial applications of online monitoring of drying processes of drug substances using NIR. Org. Process Res. Dev. 2008, 12 (2), 235-242.
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21. Gao, Y.; Olsen, K. W., Molecular dynamics of drug crystal dissolution: simulation of acetaminophen form I in water. Mol. Pharm. 2013, 10 (3), 905-917.
22. Bastin, R. J.; Bowker, M. J.; Slater, B. J., Salt selection and optimisation procedures for pharmaceutical new chemical entities. Org. Process Res. Dev. 2000, 4 (5), 427-435.
23. Black, S. N.; Collier, E. A.; Davey, R. J.; Roberts, R. J., Structure, solubility, screening, and synthesis of molecular salts. J. Pharm. Sci. 2007, 96 (5), 1053-1068.
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26. Blagden, N.; Davey, R. J., Polymorph selection: challenges for the future? Cryst. Growth Des. 2003, 3 (6), 873-885.
27. Lee, T.; Hung, S. T.; Kuo, C. S., Polymorph farming of acetaminophen and sulfathiazole on a chip. Pharm. Res. 2006, 23 (11), 2542-2555.
28. Singhal, D.; Curatolo, W., Drug polymorphism and dosage form design: a practical perspective. Adv. Drug Deliv. 2004, 56 (3), 335-347.
29. Vishweshwar, P.; McMahon, J. A.; Peterson, M. L.; Hickey, M. B.; Shattock, T. R.; Zaworotko, M. J., Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients. Chem. Commun. 2005, 2005 (36), 4601-4603.
30. Zhang, G. G. Z.; Henry, R. F.; Borchardt, T. B.; Lou, X., Efficient co-crystal screening using solution-mediated phase transformation. J. Pharm. Sci. 2007, 96 (5), 990-995.
31. Koshima, H.; Miyauchi, M., Polymorphs of a cocrystal with achiral and chiral structures prepared by pseudoseeding: tryptamine/hydrocinnamic acid. Cryst. Growth Des. 2001, 1 (5), 355-357.
32. Chen, J.-F.; Zhou, M.-Y.; Shao, L.; Wang, Y.-Y.; Yun, J.; Chew, N. Y. K.; Chan, H.-K., Feasibility of preparing nanodrugs by high-gravity reactive precipitation. Int. J. Pharm. 2004, 269 (1), 267-274.
33. Lee, T.; Zhang, C. W., Dissolution enhancement by bio-inspired mesocrystals: the study of racemic (R,S)-(±)-sodium ibuprofen dihydrate. Pharm. Res. 2008, 25 (7), 1563-1571.
34. Serajuddin, A. T. M., Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 1999, 88 (10), 1058-1066.
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36. Rohani, S., Nucleation, growth, and aggregation kinetics of potassium chloride from a continuous mixed-suspension mixed-product removal cooling crystallizer. Sep. Technol. 1993, 3 (2), 99-105.
37. Hounslow, M. J., Nucleation, growth, and aggregation rates from steady-state experimental data. AIChE J. 1990, 36 (11), 1748-1752.
38. Bohlin, M.; Rasmuson, Å. C., Modeling of growth rate dispersion in batch cooling crystallization. AIChE J. 1992, 38 (12), 1853-1863.
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40. Lawton, S.; Steele, G.; Shering, P.; Zhao, L.; Laird, I.; Ni, X.-W., Continuous crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer. Org. Process Res. Dev. 2009, 13 (6), 1357-1363.
41. Uusi-Penttilä, M. S.; Rasmuson, Å. C., Experimental study for agglomeration behaviour of paracetamol in acetone–toluene–water systems. Chem. Eng. Res. Des. 2003, 81 (4), 489-495.
42. McCabe, W. L.; Smith, J. C.; Harriott, P., Unit Operations of Chemical Engineering. 7th Ed.; McGraw-Hill, New York, 2005; Chapter 29, p 1021.
43. McCabe, W. L.; Smith, J. C.; Harriott, P., Unit Operations of Chemical Engineering. 7th Ed.; McGraw-Hill, New York, 2005; Chapter 24, pp 796-835.
44. 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.
Chapter 4
1. 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.
2. Alvarez, A. J.; Myerson, A. S., Continuous plug flow crystallization of pharmaceutical compounds. Cryst. Growth Des. 2010, 10 (5), 2219-2228.
3. Bogdan, A. R.; Poe, S. L.; Kubis, D. C.; Broadwater, S. J.; McQuade, D. T., The continuous-flow synthesis of ibuprofen. Angew. Chem. Int. Ed. 2009, 48 (45), 8547-8550.
Appendix
1. Lang, M.; Grzesiak, A. L.; Matzger, A. J., The use of polymer heteronuclei for crystalline polymorph selection. J. Am. Chem. Soc. 2002, 124 (50), 14834-14835.
2. Peterson, M. L.; Morissette, S. L.; McNulty, C.; Goldsweig, A.; Shaw, P.; LeQuesne, M.; Monagle, J.; Encina, N.; Marchionna, J.; Johnson, A.; Gonzalez-Zugasti, J.; Lemmo, A. V.; Ellis, S. J.; Cima, M. J.; Almarsson, Ö., Iterative high-throughput polymorphism studies on acetaminophen and an experimentally derived structure for form III. J. Am. Chem. Soc. 2002, 124 (37), 10958-10959.
3. Di Martino, P.; Guyot-Hermann, A. M.; Conflant, P.; Drache, M.; Guyot, J. C., A new pure paracetamol for direct compression: the orthorhombic form. Int. J. Pharm. 1996, 128 (1–2), 1-8.
4. Nichols, G.; Frampton, C. S., Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution. J. Pharm. Sci. 1998, 87 (6), 684-693.
5. Thomas, L. H.; Wales, C.; Zhao, L.; Wilson, C. C., Paracetamol form II: an elusive polymorph through facile multicomponent crystallization routes. Cryst. Growth Des. 2011, 11 (5), 1450-1452.
6. Wang, S.-L.; Lin, S.-Y.; Wei, Y.-S., Transformation of metastable forms of acetaminophen Studied by thermal fourier transform infrared (FT-IR) microspectroscopy. Chem. Pharm. Bull. 2002, 50 (2), 153-156.
7. Al-Zoubi, N.; Koundourellis, J. E.; Malamataris, S., FT-IR and Raman spectroscopic methods for identification and quantitation of orthorhombic and monoclinic paracetamol in powder mixes. J. Pharm. Biomed. Anal. 2002, 29 (3), 459-467.
8. Di Martino, P.; Conflant, P.; Drache, M.; Huvenne, J. P.; Guyot-Hermann, A. M., Preparation and physical characterization of forms II and III of paracetamol. J. Therm. Anal. Calorim. 1997, 48 (3), 447-458.
9. Moynihan, H. A.; O’Hare, I. P., Spectroscopic characterisation of the monoclinic and orthorhombic forms of paracetamol. Int. J. Pharm. 2002, 247 (1–2), 179-185.
10. Zimmermann, B.; Baranović, G., Thermal analysis of paracetamol polymorphs by FT-IR spectroscopies. J. Pharm. Biomed. Anal. 2011, 54 (2), 295-302.
11. Sacchetti, M., Thermodynamic analysis of DSC data for acetaminophen polymorphs. J. Therm. Anal. Calorim. 2000, 63 (2), 345-350.
12. Lin, S. Y.; Wang, S. L.; Cheng, Y. D., Thermally induced structural changes of acetaminophen in phase transition between the solid and liquid states monitored by combination analysis of FT-IR/DSC microscopic system. J. Phys. Chem. Solids 2000, 61 (11), 1889-1893.

指導教授

李度(Tu Lee)

審核日期

2013-7-15

推文