Process Intensification for Pharmaceutical Granules Preparation Using Spherical Agglomeration

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陳峙瑋(Chih-Wei Chen) 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

(Process Intensification for Pharmaceutical Granules Preparation Using Spherical Agglomeration)

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摘要(中)

本論文介紹了目前製藥行業的概況，包括：法規、批次式/連續式製程，以及藥物的常見劑型，其中，化學工程（化工）在製藥業中扮演著相當重要的角色，特別是在生產製造中更是重要。從活性藥物成分（API）的生產到下游的製劑配方的製造，許多的單元操作都與化工的專業高度相關，例如：藥物的化學合成、發酵、純化、分離及製劑等所有生產加工過程，都會對最終藥品的品質產生重大的影響。
許多粉末性質，例如：顆粒大小、外觀形狀、密度、粉末流動性和可壓縮性等，對於藥物產品的可製造性、加工性及生物可利用度，皆有高度的影響。一般而言，在API生產流程，從結晶製程獲得的API粉末可能會具有不佳的粉末加工性質，可透過研磨或造粒加工製程，將顆粒磨小或增大以改善粉末性質。然而，API的結晶和研磨/造粒製程可透過球晶製程加以整合，球晶製程是一種與粉末製造相關的技術，且具新穎性的製程強化策略，它可以改善由結晶製程產生的許多特性，例如：顆粒尺寸分佈及下游加工製程的效率。
本論文研究了API藥物粉末的球晶製程，包括：從反應、結晶至球晶的三合一強化製程，以及攪拌混合效應對球晶製程的影響。
利用0.5 公升大並具有夾套的玻璃反應槽中，進行三個獨立的步驟，即：反應、結晶與球晶的三合一強化製程，可直接從酯化反應中成功製備出高純度、同晶型、球形和流動性佳的富馬酸二甲酯顆粒，富馬酸二甲酯是透過富馬酸與甲醇的酯化反應，並以硫酸作為催化劑製備而得，富馬酸二甲酯的球晶顆粒的力學性能，例如：密度，孔隙率、Carr’s index、易碎性和破裂強度將詳細地研究與比較。此外，並在10 公升大的玻璃反應槽中驗證了三合一強化製程的放大生產之概念，根據實驗結果得知，球晶的製造大幅提升了粉末的可製造性及加工性，如：流動性，混均勻性和可壓縮性。
為提升球晶製程之產率，富馬酸二甲酯的球晶顆粒已成功在配有Maxblend攪拌葉片的2公升大及10 公升大的攪拌槽中製備而得。根據實驗顯示，Maxblend攪拌葉片可產生良好的混合效果，並增加顆粒之間的碰撞機率。此外，從2公升大及10 公升大的攪拌槽中製備而得球晶顆粒尺寸分佈沒有顯著的差異。

摘要(英)

A brief introduction to the pharmaceutical industry including regulation, batch/continuous manufacturing processes, and common dosage forms in pharmaceuticals was presented. Chemical engineering plays a crucial role in the pharmaceutical industry, especially for drug manufacturing. From active pharmaceutical ingredient (API) manufacturing to the downstream formulation, various unit operations are highly related to chemical engineering disciplines. For example, all of the manufacturing processed such as chemical synthesis, fermentation, purification, separation, and formulation would influence significantly the quality of the final drug product.
Powder properties such as particle size, shape, density, flowability, and compressibility are of importance in manufacturability, processibility, and bioavailability of drug products. Traditionally, powders obtained from API manufacturing (i.e. crystallization) may have adverse quality, size reduction (i.e. milling) or size enlargement (i.e. granulation) processes would be carried out to improve powder properties. However, crystallization and milling/granulation of APIs can be intensified to spherical crystallization. Spherical crystallization is a novel process intensification strategy related to powder manufacturing, and that can improve many properties produced by crystallization, such as size distribution, and downstream process efficiency.
In this dissertation, the spherical agglomeration processes for preparing granules of API drug including three-in-one intensified process of reaction, crystallization and spherical agglomeration, and mixing effect on spherical agglomeration.
Pure, isomorphic, round and free-flowing dimethyl fumarate granules were successfully produced directly from esterification through the three-in-one intensified process of three distinctive steps of reaction, crystallization and spherical agglomeration in a 0.5 L-sized jacketed glass stirred tank. Dimethyl fumarate was prepared by sulfuric acid-catalyzed esterification of fumaric acid with methanol. The mechanical properties such as density, porosity Carr’s index, friability and fracture force of round dimethyl fumarate granules were thoroughly studied and compared. The concept of scale-up for three-in-one intensified process was also verified in 10 L-sized jacketed glass stirred tank. Powder manufacturability such as flowability, blend uniformity and compressibility had been substantially enhanced by spherical agglomeration.
The spherical agglomerates of dimethyl fumarate have been successfully prepared in both 2 L-sized and 10 L-sized stirred vessels equipped with Maxblend impeller as well. Maxblend impeller create good mixing performance to increase the collision probability between particles. No significant difference on agglomerate size distribution was observed in comparison of 2 L-sized and 10 L-sized scales.

關鍵字(中)

★ 製程強化
★ 球晶
★ 粉末技術
★ 反溶劑結晶
★ 活性藥物成份

關鍵字(英)

★ Process Intensification
★ Spherical Agglomeration
★ Powder Technology
★ Anti-Solvent Crystallization
★ Active Pharmaceutical Ingredient

論文目次

Table of Contents
摘要 i
Abstract iii
Acknowledgement v
Publications vii
List of Figures xiii
List of Tables xx
List of Schemes xxi
Chapter 1 The Role of Chemical Engineering in Pharmaceutical Industry 1
1.1 Pharmaceutical Industry Trend 1
1.2 Pharmaceutical Processing － Batch or Continuous Process 7
1.3 Common Dosage Forms in Pharmaceuticals 12
1.4 Unit Operations in Pharmaceutical Production 15
1.4.1 API Manufacturing 17
1.4.2 Formulation 19
1.5 Powder Technology 21
1.6 Spherical Crystallization 24
1.6.1 Challenge of Spherical Crystallization Technique 29
1.7 Mixing Effect in Mechanically Agitated Vessels 32
1.8 References 40
Chapter 2 Experimental Materials and Methods 52
2.1 Chemicals and Solvents 52
2.2 Apparatus for Three-in-One Intensified Process, Recrystallization and Spherical Agglomeration 53
2.3 Three-in-One Intensified Process of Reaction, Crystallization and Spherical Agglomeration of Dimethyl Fumarate in 0.5 L-Sized Stirred Tank 55
2.4 Disconnection of Spherical Agglomeration of Dimethyl Fumarate in 0.5 L-Sized Stirred Tank 56
2.5 Large Scale for Three-in-One Intensified Process of Dimethyl Fumarate 57
2.6 Recrystallization of Dimethyl Fumarate in 2 L-Sized Stirred Tank 58
2.7 Preparation for Spherical Agglomerates of Dimethyl Fumarate in 2 L-Sized Stirred Tank by Using Recrystallization 59
2.8 Spherical Agglomeration of Dimethyl Fumarate in 10 L-Sized Stirred Tank by Using Recrystallization 60
2.9 Analytical Methods for Reaction Kinetics Study 61
2.9.1 Gravimetric Analysis 61
2.9.2 Nuclear Magnetic Resonance (NMR) Analysis 62
2.9.3 Solubility Test 63
2.10 Sieve Analysis Method 63
2.11 Mechanical Properties of Spherical Agglomerates 64
2.11.1 Density of Spherical Agglomerates 64
2.11.2 Porosity of Spherical Agglomerates 64
2.11.3 Carr’s Index 65
2.11.4 Friability 65
2.11.5 Particle Strength 66
2.11.6 Tabletability 66
2.12 Dissolution Test 66
2.13 Analytical Instrumentations 67
2.13.1 Thermocouple 67
2.13.2 Nuclear Magnetic Resonance Spectroscopy (NMR) 67
2.13.3 Gas Chromatography–Mass Spectroscopy (GC-MS) 68
2.13.4 High Performance Liquid Chromatography (HPLC) 68
2.13.5 Gas Chromatography (GC) 69
2.13.6 Fourier Transform Infrared (FT-IR) Spectroscopy 69
2.13.7 Differential Scanning Calorimetry (DSC) 69
2.13.8 Powder X-Ray Diffraction (PXRD) 70
2.13.9 Single Crystal X-ray Diffraction (SXD) 70
2.13.10 Optical Microscopy (OM) 70
2.13.11 Ultraviolet Visible (UV/Vis) Spectrophotometer 71
2.14 References 72
Chapter 3 Results and Discussion 74
3.1 Round Granules of Dimethyl Fumarate by Three-in-One Intensified Process of Reaction, Crystallization and Spherical Agglomeration in a Common Stirred Tank 74
3.1.1 Reaction 79
3.1.2 Crystallization 84
3.1.3 Spherical Agglomeration 89
3.1.4 Dissolution Performance 94
3.1.5 Analysis and Characterization 96
3.1.6 Effects of Tank Size 102
3.2 Mixing Effect on Spherical Agglomeration in Dimethyl Fumarate Granules 104
3.2.1 Effect of Impeller Configuration 106
3.2.2 Large Scale for Spherical Agglomeration 115
Supplementary Information 118
Chemical Kinetics Experiments 118
Reaction Enthalpy 128
3.3 References 140
Chapter 4 Conclusions and Future Works 147
4.1 Conclusions 147
4.2 Future Works 149

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Chapter 2
1. 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.
2. Zwietering, T. N. Suspending of solid particles in liquid by agitators. Chem. Eng. Sci. 1958, 8(3-4), 244-253.
3. Chen, C. W.; Lee, T. Round granules of dimethyl fumarate by three-in-one intensified process of reaction, crystallization, and spherical agglomeration in a common stirred tank. Org. Process Res. Dev. 2017, 21(9), 1326-1339.
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7. 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.
8. Tiong, N.; Elkordy, A. A. Effects of liquisolid formulations on dissolution of naproxen. Eur. J. Pharm. Biopharm. 2009, 73(3) 373-384.
9. Kooijman, H.; Sprengers, J. W.; Agerbeek, M. J.; Elsevier, C. J.; Spek, A. L. Dimethyl fumarate. Acta Cryst. 2004, E60, o917-o918.

Chapter 3
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16. Tahara, K.; O’Mahony, M.; Myerson, A. S. Continuous spherical crystallization of albuterol sulfate with solvent recycle system. Cryst. Growth Des., 2015, 15(10), 5149-5156.
17. Lee, T.; Su, Y. C.; Hou, H. J.; Hsieh, H. Y. Spherical crystallization for lean solid-dose manufacturing (Part I). Pharm. Technol. 2010, March, 72-75.
18. 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.
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指導教授

李度(Tu Lee)

審核日期

2020-7-29

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