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。

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.

Chapter 1
1. Exploring the Drug Development Process (https://www.technologynetworks.com/drug-discovery/articles/exploring-the-drug-development-process-331894, last assessed on June 30, 2020).
2. 505(b)(1) and 505(b)(2) Pathways for new drugs: When to use & common misconceptions (https://www.nuventra.com/resources/blog/505b1-505b2-pathways-for-new-drugs/, last assessed on June 30, 2020).
3. What is the difference between ANDAs & 505(b)(2) NDAs (https://www.nuventra.com/resources/blog/505b2-nda-versus-anda/, last assessed on June 30, 2020).
4. A History of Medical Device Regulation & Oversight in the United States (https://www.fda.gov/medical-devices/overview-device-regulation/history-medical-device-regulation-oversight-united-states, last assessed on June 30, 2020).
5. Patent linkage: Balancing patent protection and generic entry (https://www.drugpatentwatch.com/blog/patent-linkage-resolving-infringement/, last assessed on June 30, 2020).
6. Appendix A: Glossary of terms. In Generic drug entry prior to patent expiration: An FTC study; United States. Federal Trade Commission, 2002; pp. A-1.
7. Intricacies of the 30-Month Stay in Pharmaceutical Patent Cases (https://www.americanpharmaceuticalreview.com/Featured-Articles/348913-Intricacies-of-the-30-Month-Stay-in-Pharmaceutical-Patent-Cases/?catid=25273, last assessed on June 30, 2020).
8. Generic drugs market: Global industry trends, share, size, growth, opportunity and forecast 2020-2025 (https://www.imarcgroup.com/generic-drug-manufacturing-plant, last assessed on June 30, 2020).
9. GMP management of pharmaceutical manufacturers (https://www.fda.gov.tw/ENG/siteListContent.aspx?sid=10387&id=28055, last assessed on June 30, 2020).
10. Accession of Taiwan FDA to PIC/S- Providing a major boost to the Taiwan pharmaceutical industry (https://www.mohw.gov.tw/cp-115-36772-2.html, last assessed on June 30, 2020).
11. Olmsted, J. III. Synthesis of Aspirin: A general chemistry experiment. J. Chem. Educ. 1998, 75(10), 1261-1263.
12. 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.
13. Fischer, R.; Stoger, E.; Schillberg, S.; Christou, P.; Twyman, R. M. Plant-based production of biopharmaceuticals. Curr. Opin. Plant Biol. 2004, 7(2), 152-158.
14. Krishnamurti, C.; Rao, S. C. The isolation of morphine by Serturner. Indian J. Anaesth. 2016, 60(11), 861-862.
15. Achan, J.; Talisuna, A. O.; Erhart, A.; Yeka, A.; Tibenderana, J. K.; Baliraine, F. N.; Rosenthal, P. J.; D'Alessandro, U. Quinine, an old anti-malarial drug in a modern world: Role in the treatment of malaria. Malar. J. 2011, 10(144), 1-12.
16. Covic, A.; Kuhlmann, M. K. Biosimilars: recent developments. Int. Urol. Nephrol. 2007, 39(1), 261-266.
17. Mascia, S.; Heider, P. L.; Zhang, H.; Lakerveld, R.; Benyahia, B.; Barton, P. I.; Braatz, R. D.; Cooney, C. L.; Evans, J. M. B.; Jamison, T. F.; Jensen, K. F.; Myerson, A. S.; Trout, B. L. End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. Angew. Chem. Int. Ed. 2013, 52(47), 12359-12363.
18. Poechlauer, P.; Manley, J.; Broxterman, R.; Gregertsen, B.; Ridemark, M. Continuous processing in the manufacture of active pharmaceutical ingredients and finished dosage forms: An industry perspective. Org. Process Res. Dev. 2012, 16(10), 1586-1590.
19. Pharmaceutical Dosage Forms (https://makromedicine.com/blog/pharmaceutical-dosage-forms, last assessed on June 30, 2020).
20. Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Greener approaches to organic synthesis using microreactor technology. Chem. Rev. 2007, 107(6), 2300-2318.
21. Zhao, C. X.; He, L.; Qiao, S. Z.; Middelberg, A. P. J. Nanoparticle synthesis in microreactors. Chem. Eng. Sci. 2011, 66, 1463-1479.
22. Yoshida, J.-i.; Heejin Kim, H.; Nagaki, A. Green and sustainable chemical synthesis using flow microreactors. ChemSusChem, 2011, 4(3), 331-340.
23. Pohar, A.; Plazl, I. Process intensification through microreactor application. Chem. Biochem. Eng. Q. 2009, 23(4), 537-544.
24. Sawai, Y.; Yamano, M. Green processes for peptide mimetic diabetic drugs. In Green chemistry in the pharmaceutical industry; Dunn, P. J., Wells, A., Williams, M. T., Eds.; WILEY-VCH, 2010; pp. 179-195.
25. API Purification (http://www.pharmtech.com/api-purification, last assessed on June 30, 2020).
26. Fahrner, R. L.; Knudsen, H. L.; Basey,C. D.; Galan, W.; Feuerhelm, D.; Vanderlaan, M.; Blank, G. S. Industrial purification of pharmaceutical antibodies: development, operation, and validation of chromatography processes. Biotechnol. Genet. Eng. Rev. 2001, 18(1), 301-327.
27. Lee, H. L.; Lin, H. Y.; Lee, T. Large-scale crystallization of a pure metastable polymorph by reaction coupling. Org. Process Res. Dev. 2014, 18(4), 539-545.
28. Yang, Y.; Nagy, Z. K. Advanced control approaches for combined cooling/antisolvent crystallization in continuous mixed suspension mixed product removal cascade crystallizers. Chem. Eng. Sci. 2015, 127, 362-373.
29. Besenhard, M. O.; Neugebauer, P.; Scheibelhofer, O.; Khinast, J. G. Crystal engineering in continuous plug-flow crystallizers. Cryst. Growth Des. 2017, 17(12), 6432-6444.
30. 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.
31. Majekodunmi, S. O.; Olorunsola, E. O. Review of some recent advances on filtration in pharmaceutical industry IOSR J. Pharm. Biol. Sci. 2014, 9(4), 30-38.
32. Filtration and drying in agitated Nutsche filter process 3D animation (https://www.youtube.com/watch?v=I9qRGB1LFic, last assessed on June 30, 2020).
33. Capellades, G.; Neurohr, C.; Azad, M.; Brancazio, D.; Rapp, K.; Hammersmith, G.; Myerson, A. S. A compact device for the integrated filtration, drying, and mechanical processing of active pharmaceutical ingredients J. Pharm. Sci. 2020, 109(3), 1365-1372.
34. Byrn, S.; Morris, K.; Comella, S. Reducing time to market with a science-based management strategy. Pharm. Tech. 2005, 5, 46-56.
35. Qiu, Y.; Chen, Y.; Zhang, G. G. Z.; Yu, L.; Mantri, R. V. Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice. 2nd Ed.; Academic Press, 2016.
36. Simmons, D. M. Punch Sticking: Factors and Solutions. In Chemical Engineering in the Pharmaceutical Industry: Drug Product Design, Development, and Modeling; am Ende, M. T., am Ende, D. J., Eds; John Wiley & Sons, Inc. Hoboken, 2019; pp.227-244.
37. Chattoraj, S.; Sun, C. C. Crystal and particle engineering strategies for improving powder compression and flow properties to enable continuous tablet manufacturing by direct compression. J. Pharm. Sci. 2018, 107(4), 968-974.
38. Shanmugam, S. Granulation techniques and technologies: recent progresses. BioImpacts 2015, 5(1), 55-63.
39. What does the color of medication mean? (https://www.singlecare.com/blog/the-color-of-medicine/, last assessed on June 30, 2020).
40. Particle size specifications for solid oral dosage forms: A regulatory perspective (https://www.americanpharmaceuticalreview.com/Featured-Articles/36779-Particle-Size-Specifications-for-Solid-Oral-Dosage-Forms-A-Regulatory-Perspective/, last assessed on June 30, 2020)
41. Jain, R. A.; Brito, L.; Straub, J. A.; Tessier, T.; Bernstein, H. Effect of powder processing on performance of fenofibrate formulations. Eur. J. Pharm. Biopharm. 2008, 69(2), 727-734.
42. Singh, A.; Worku, Z. A.; Van den Mooter, G. Oral formulation strategies to improve solubility of poorly water-soluble drugs. Expert Opin. Drug Deliv. 2011, 8(10), 1361-1378.
43. Khadka, P.; Ro, J.; Kim, H.; Kim, I.; Kim, J. T.; Kim, H.; Cho, J. M.; Yun, G.; Lee, J. Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J. Pharm. Sci. 2014, 9(6), 304-316.
44. Joshi, J. T. A review on micronization techniques. J. Pharm. Sci. Technol. 2011, 3(7), 651-681.
45. Varshosaz, J.; Ghassami, E.; Ahmadipour, S. Crystal engineering for enhanced solubility and bioavailability of poorly soluble drugs. Curr. Pharm. Des. 2018, 24(21), 2473-2496.
46. Hu, J.; Rogers, T. L.; Brown, J.; Young, T.; Johnston, K. P.; Williams, R. O. Improvement of dissolution rates of poorly water soluble APIs using novel spray freezing into liquid technology. Pharm. Res. 2002, 19, 1278-1284.
47. 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.
48. Kovačič, B.; Vrečer, F.; Planinšek, O. Spherical crystallization of drugs. Acta Pharm. 2012, 62, 1-14.
49. Bharti, N.; Bhandari, N.; Sharma, P.; Singh, K.; Kumar, A. Spherical crystallization: A novel drug delivery approach. Asian J. Biomed. Pharm. Sci. 2013, 3(18), 10-16.
50. Katta, J.; Rasmuson, Å. C. Spherical crystallization of benzoic acid. Int. J. Pharm. 2008, 348(1-2), 61-69.
51. McKeown, R. R. Spherical agglomeration of API: Screening protocol, process design and scale-up, 2013 AIChE Annual Meeting, San Francisco, CA, Nov. 3-8, 2013; American Institute of Chemical Engineers, New York, 2013.
52. Kawashima, Y.; Niwa, T.; Handa, T.; Takeuchti, H.; Iwamoto, T.; Itoh, K. Preparation of controlled-release microspheres of ibuprofen with acrylic polymers by a novel quasi-emulsion solvent diffusion method. J. Pharm. Sci. 1989, 78(1), 68-72.
53. Puechagut, H. G.; Bianchotti, J.; Chiale, C. A. Preparation of norfloxacin spherical agglomerates using the ammonia diffusion system. J. Pharm. Sci. 1998, 87(4), 519-523.
54. Kawashima, Y.; Handa, T.; Takeuchi, H.; Okumura, M.; Katou, H.; Nagata, O. Crystal modification of phenytoin with polyethylene glycol for improving mechanical strength, dissolution rate and bioavailability by a spherical crystallization technique. Chem. Pharm. Bull. 1986, 34(8), 3376-3383.
55. Pawar, A.; Paradkar, A.; Kadam, S.; Mahadik, K. Crystallo-co-agglomeration: A novel technique to obtain ibuprofen-paracetamol agglomerates. AAPS PharmSciTech 2004, 5(3), 57-64.
56. Thati, J.; Rasmuson, Å. C. Particle engineering of benzoic acid by spherical agglomeration. Eur. J. Pharm. Sci. 2012, 45(5), 657-667.
57. Kawashima, Y.; Furukawa, K.; Takenaka, H. The physicochemical parameters determining the size of agglomerate prepared by the wet spherical agglomeration technique. Powder Technol. 1981, 30(2), 211-216.
58. Thati, J.; Rasmuson, A. C. On the mechanisms of formation of spherical agglomerates. Eur. J. Pharm. Sci. 2011, 42(4), 365-379.
59. Blandin, A. F.; Mangin, D.; Rivoire, A.; Klein, J. P.; Bossoutrot, J. M. Agglomeration in suspension of salicylic acid fine particles: Influence of some process parameters on kinetics and agglomerate final size. Powder Technol. 2003, 130(1-3), 316−323.
60. Maghsoodi, M.; Yari, Z. Effect of temperature on wet agglomeration of crystals. Iran J. Basic Med. Sci. 2014, 17(5), 344-350.
61. Varshosaz, J.; Tavakoli, N.; Salamat, F. A. Enhanced dissolution rate of simvastatin using spherical crystallization technique. Pharm. Dev. Technol. 2011, 16(2), 529-535.
62. Gyulai, O.; Szabó-Révész, P.; Aigner, Z. Comparison study of different spherical crystallization methods of ambroxol hydrochloride. Cryst. Growth Des. 2017, 17(10), 5233-5241.
63. Orlewski, P. M.; Ahn, B.; Mazzotti, M. Tuning the particle sizes in spherical agglomeration. Cryst. Growth Des. 2018, 18(3), 6257-6265.
64. Peña, R.; Jarmer, D. J.; Burcham, C. L.; Nagy, Z. K. Further understanding of agglomeration mechanisms in spherical crystallization systems: Benzoic acid case study. Cryst. Growth Des. 2019, 19(3), 1668-1679.
65. 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.
66. Tahara, K.; Kono, Y.; Myerson, A. S.; Takeuchi, H. Development of continuous spherical crystallization to prepare fenofibrate agglomerates with impurity complexation using mixed-suspension, mixed-product removal crystallizer. Cryst. Growth Des. 2018, 18(11), 6448-6454.
67. Peña, R.; Nagy, Z. K. Process intensification through continuous spherical crystallization using a two-stage mixed suspension mixed product removal (MSMPR) system. Cryst. Growth Des. 2015, 15(9), 4225-4236.
68. Peña, R,; Oliva, J.A.; Burcham, C. L.; Jarmer, D. J.; Nagy, Z. K. Process intensification through continuous spherical crystallization using an oscillatory flow baffled crystallizer. Cryst. Growth Des. 2017, 17(9), 4776-4784.
69. Oliva, J.A.; Wu, W.-L.; Greene, M. R.; Pal, K.; Nagy, Z. K. Continuous spherical crystallization of lysozyme in an oscillatory baffled crystallizer using emulsion solvent diffusion in droplets. Cryst. Growth Des. 2020, 20(2), 934-947.
70. Wood, B.; Girard, K.P.; Polster, C.S.; Croker, D.M. Progress to date in the design and operation of continuous crystallization processes for pharmaceutical applications. Org. Process Res. Dev. 2019, 23(2), 122-144.
71. 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.
72. Atherton, J. H. Physicochemical data requirements for the design of fine chemical processes: Acquisition and application. In Pharmaceutical process development: Current chemical and engineering challenge; Blacker, A. J., Williams, M. T., Eds.; Royal Society of Chemistry: Cambridge, 2011; pp. 178-208.
73. Torbacke, M.; Rasmuson, Å. C. Influence of different scales of mixing in reaction crystallization. Chem. Eng. Sci. 2001, 56(7), 2459-2473.
74. Pedrosa, S. M. C. P.; Nunhez, J. R. The behavior of stirred vessels with anchor type impellers. Comput. Chem. Eng. 2000, 24(2-7), 1745-1751.
75. Doran, Pauline M. Chapter 8 - Mixing. In Bioprocess engineering principles (second edition); Elsevier: Waltham, MA, 2013; pp. 255-332.
76. Arjunwadkar, S. J.; Sarvanan, K.; Kulkarnia, P. R.; Pandit, A. B. Gas-liquid mass transfer in dual impeller bioreactor. Biochem. Eng. J. 1998, 1(2), 99-106.
77. Sharma, R. N.; Shaikh, A. A. Solid suspension in stirred tanks with pitched blade turbines. Chem. Eng. Sci. 2003, 58(10), 2123-2140.
78. Jirout, T.; Rieger, F. Impeller design for mixing of suspensions. Chem. Eng. Res. Des. 2011, 89(7), 1144-1151.
79. Zwietering, T. N. Suspending of solid particles in liquid by agitators. Chem. Eng. Sci. 1958, 8(3-4), 244-253.
80. Rieger, F.; Ditl, P. Suspension of solid particles. Chem. Eng. Sci. 1994, 49(14), 2219-2227.
81. Rao, K. S. M. S. R.; Rewatkar, V. B.; Joshi, J.B. Critical impeller speed for solid suspension in mechanically agitated contactors. AIChE J. 1988, 34(8), 1332-1340.
82. Impellers (https://www.ekato.com/en/products/agitator-components/impellers/, last assessed on June 30, 2020).
83. Kresta, S. M.; Wood, P. E. The mean flow field produced by a 45° pitched blade turbine: Changes in the circulation pattern due to off bottom clearance. Can. J. Chem. Eng. 1993, 71(1), 42-53.
84. Mao, D.-M.; Feng, L.-F.; Wang, K.; Li, Y.-L. The mean flow field generated by a pitched blade turbine: Changes in the circulation pattern due to impeller geometry. Can. J. Chem. Eng. 1997, 75(2), 307-316.
85. Qiao, S.; Wang, R.; Yang, X.; Yan, Y. CFD prediction of mean flow field and impeller capacity for pitched blade turbine. Trans. Tianjin Univ. 2015, 21, 250-258.
86. Tsui, Y.-Y.; Chou, J.-R.; Hu, Y.-C. Blade angle effects on the flow in a tank agitated by the pitched-blade turbine. J. Fluid Eng. 2006, 128(4), 774-782.
87. Topic: Is pumping rate a good measure of mixer performance? (https://www.chemicalprocessing.com/experts/mixing/show/1095, last assessed on June 30, 2020)
88. Fradette, L.; Thome, G.; Tanguy, P.; Takenaka, K. Power mixing time study involving a Maxblend impeller with viscous Newtonian and non-Newtonian fluids. Chem. Eng. Res. Des. 2007, 85(11), 1514-1523.

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.
4. Yadav, G. D.; Thathagar, M. B. Esterification of maleic acid with ethanol over cation-exchange resin catalysts. React. Funct. Polym. 2002, 52(2), 99-110.
5. 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.
6. Lamas, J. P.; Sanchez-Prado, L.; Regueiro, J.; Llompart, M.; Garcia-Jares, C. Determination of dimethyl fumarate and other potential allergens in desiccant and antimould sachets. Anal Bioanal Chem. 2009, 394(8), 2231-2239.
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
1. Mollan, M. J.; Lodaya, M. Continuous processing in pharmaceutical manufacturing. Pharm. Manuf. Mag. 2004. (http://www.pharmamanufacturing.com/assets/Media/MediaManager/ContinuousProcessinginPharmaManufacturing.doc, last assessed on June 30, 2020).
2. Wall Street Journal "Factory shift: New prescription for drug makers: Update the plants." September 3, 2003.
3. Plumb, K. Continuous processing in the pharmaceutical industry changing the mind set. Trans IChemE, Part A, Chem. Eng. Res. Des. 2005, 83(A6), 730-738.
4. Leane, M.; Pitt, K.; Reynolds, G. A proposal for a drug product manufacturing classification system (MCS) for oral solid dosage forms. Pharm. Dev. Technol. 2015, 20(1), 12-21.
5. Parikh, D. M. Continuous granulation technology trends: seeking a smooth path and avoiding dead ends. Contract Pharma 2016, June, 82-85.
6. Shanmugam, S. Granulation techniques and technologies: Recent progresses. BioImpacts 2015, 5(1), 55-63.
7. Kleinebudde, P. Roll compaction/dry granulation: Pharmaceutical applications. Eur. J. Pharm. Biopharm. 2004, 58(2), 317-326.
8. Vervaet, C.; Remon, J. P. Continuous granulation in the pharmaceutical industry. Chem. Eng. Sci. 2005, 60(14), 3949-3957.
9. Pasquali, I.; Bettini, R.; Giordano, F. Supercritical fluid technologies: An innovative approach for manipulating the solid-state of pharmaceuticals. Adv. Drug Deliv. Rev. 2008, 60(3), 399-410.
10. Mackaplow, M. B.; Rosen, L. A.; Michaels, J. N. Effect of primary particle size on granule growth and endpoint determination in high-shear wet Granulation. Powder Technol. 2000, 108(1), 32-45.
11. Bardin, M.; Knight, P. C.; Seville, J. P. K. On control of particle size distribution in granulation using high-shear mixers. Powder Technol. 2004, 140(3), 169-175.
12. Park, J.-B.; Kang, C.-Y.; Kang, W.-S.; Choi, H.-G.; Han, H.-K.; Lee, B.-J. New investigation of distribution imaging and content uniformity of very low dose drugs using hot-melt extrusion method. Int. J. Pharm. 2013, 458(2), 245-253.
13. Kawashima, Y.; Capes, C. E. Experimental study of the kinetics of spherical agglomeration in a stirred Tank. Powder Technol. 1974, 10(1-2), 85-92.
14. Kawashima, Y.; Okumura, M.; Takenaka, H. Spherical crystallization: Direct spherical agglomeration of salicylic acid crystals during crystallization. Science 1982, 216(4550), 1127-1128.
15. Peña, R.; Nagy, Z. K. Process intensification through continuous spherical crystallization using a two-stage mixed suspension mixed product removal (MSMPR) system. Cryst. Growth Des. 2015, 15(9), 4225-4236
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.
19. Li, J.-S.; Wu, S.-W.; Lu, K.-T. Study on preparation of intensive and spherical high bulk density nitroguanidine with controllable particle size. Propellants Explos. Pyrotech. 2016, 41(2), 312-320.
20. Jitkar, S.; Thipparabonia, R.; Chaven, R. B.; Shastri, N. R. Spherical agglomeration of platy crystals: curious case of etodolac. Cryst. Growth Des. 2016, 16(7), 4034-4042.
21. 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, 809-817.
22. Quon, J. L.; Chadwick, K.; Wood, G. P. F.; Sheu, I.; Brettmann, B. K.; Myerson, A. S.; Trout, B. L. Templated nucleation of acetaminophen on spherical excipient agglomerates. Langmuir 2013, 29(10), 3292-3300.
23. Toddy, A. I.; Badruddoza, A. Z. M.; Zheng, L.; Alan Hatton, T.; Gunawan, R.; Rajagopalan, R.; Khan, S. A. Spherical crystallization of glycine from monodisperse microfluidic emulsion. Cryst. Growth Des. 2012, 12(8), 3977-3982.
24. Zhang, H.; Chen, Y.; Wang, J.; Gong, J. Investigation on the spherical crystallization process of cefotaxime sodium. Ind. Eng. Chem. Res. 2010, 49(3), 1402-1411.
25. Luo, J.; Kong, F.; Ma, X. Role of aspartic acid in the synthesis of spherical vaterite by the Ca(OH)2-CO2 reaction. Cryst. Growth Des. 2016, 16(2), 728-736.
26. Lee, T.; Tsai, Y. C.; Lee, H. L.; Lin, T. Y.; Chang, Y. H. Metal-organic framework engineering: Directed assembly from molecules to spherical agglomerates. J. Taiwan Inst. Chem. Eng. 2016, 62, 10-20.
27. Jarvis, L. M. The year in new drugs. C&EN 2014, 92(4), 10-13.
28. Guzowski, J.; Kiesman, W.; Irdam, E. Process for preparing high purity and crystalline dimethyl fumarate. U.S. Patent 9422226 B2, August 23, 2016.
29. Kooijman, H.; Sprengers, J. W.; Agerbeek, M. J.; Elsevier, C. J.; Spek, A. L. Dimethyl fumarate. Acta Cryst. 2004, E60, o917-o918.
30. Rönnback, R.; Salmi, T.; Vuori, A.; Haario, H.; Lehtonen, J.; Sundqvist, A.; Tirronen, E. Development of a kinetic model for the esterification of acetic acid with methanol in the presence of a homogeneous acid catalyst. Chem. Eng. Sci. 1997, 52(19), 3369-3381.
31. 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.
32. 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.
33. Guzowski, Jr., J. P.; Delaney, E. J.; Humora, M. J.; Irdam, E.; Kiesman, W. F.; Kwok, A.; Moran, A. D. Understanding and control of dimethyl sulfate in a manufacturing process: kinetic modeling of a fischer esterification catalyzed by H2SO4. Org. Process Res. Dev. 2012, 16(2), 232-239.
34. Anderson, R. J.; Bendell, D. J.; Groundwater, P. W. Nuclear magnetic resonance spectroscopy. In Organic Spectroscopic Analysis; Abel, E. W. Royal Society of Chemistry, Cambridge, 2004; pp.60-64.
35. Blandin, A.-F.; Rivoire, A.; Mangin, D.; Klevin. J.-P.; Bossoutrot, J.-M. Using in situ image analysis to study the kinetics of agglomeration in suspension. Part. Part. Syst. Charact. 2000, 17, 16-20.
36. Thati, J.; Rasmuson, Å. C. On the mechanisms of formation of spherical agglomerates. Eur. J. Pharm. Sci. 2011, 42(4), 365-379.
37. Thati, J.; Rasmuson, Å. C. Particle engineering of benzoic acid by spherical agglomeration. Eur. J. Pharm. Sci. 2012, 45(5), 657-667.
38. Blandin, A. F.; Mangin, D.; Rivoire, A.; Klein, J. P.; Bossoutrot, J. M. Agglomeration in suspension of salicylic acid fine particles: Influence of some process parameters on kinetics and agglomerate final Size. Powder Technol. 2003, 130(1-3), 316-323.
39. Nocent, M.; Bertocchi, L.; Espitalier, F.; Baron, M.; Couarraze, G. Definition of a solvent system for spherical crystallization of salbutamol sulfate by quasi-emulsion solvent diffusion (QESD) method. J. Pharm. Sci. 2001, 90(10), 1620-1627.
40. Katta, J.; Rasmuson, Å. C. Spherical crystallization of benzoic acid. Inter. J. Pharm. 2008, 348(1-2), 61-69.
41. Ghotli, R. A.; Shafeeyan, M. S.; Abbasi, M. R.; Raman, A. A. A. R.; Ibrahim, S. Macromixing study for various designs of impellers in a stirred vessel. Chem. Eng. Process. 2020, 148, 107794
42. Hidalgo-Millan, A.; Zenit, R,; Palacios, C.; Palacios, C.; Yatomic, R.; Horiguchi, H.; Tanguy, P. A.; Ascanio, G. On the hydrodynamics characterization of the straight Maxblend® impeller with Newtonian fluids. Chem. Eng. Res. Des. 2012, 90(9), 1117-1128.
43. What is MAXBLEND? (https://www.shi-pe.shi.co.jp/english/products/mixing/maxblendclub/mbabout/, last assessed on June 30, 2020).
44. Karimi, A.; Golbabaei, F.; Mehrnia, M. R.; Neghab, M.; Mohammad, K.; Nikpey, A.; Pourmand, M. R. Oxygen mass transfer in a stirred tank bioreactor using different impeller configurations for environmental purposes. Iran. J. Environ. Health Sci. Eng. 2013, 10, 6.
45. Xu, Z.; Jin, Z.; Liu, B.; Bengt, S. Experimental investigation on solid suspension performance of coaxial mixer in viscous and high solid loading systems. Chem. Eng. Sci. 2019, 208, 115144.
46. Chapple, D.; Kresta, S. M.; Wall, A.; Afacan, A. The effect of impeller and tank geometry on power number for a pitched blade turbine. Chem. Eng. Res. Des. 2002, 80(4), 364-372.
47. McKeown, R. R. Spherical agglomeration of API: Screening protocol, process design and scale-up, 2013 AIChE Annual Meeting, San Francisco, CA, Nov. 3-8, 2013; American Institute of Chemical Engineers, New York, 2013.
48. Zweitering, Th. N. Suspension of solid particles in liquids by agitators. Chem. Eng. Sci. 1958, 8(3-4), pp. 244-253.
49. Fogler, H. S. Elements of Chemical Reaction Engineering, 3rd Ed.; Prentice Hall International Series: New York, NY, 2000; pp 253-292.
50. Matos, M. A. R.; Miranda, M. S.; Morais, V. M. F.; Liebman, J. F. Org. Biomol. Chem. 2003, 1(16), 2930-2934.