罌粟鹼是一種昂貴的藥物，可從鴉片或複雜的化學合成獲得，它與大部分的藥物一樣具有低溶解度的缺點，因此將罌粟鹼游離鹼轉化成罌粟鹼鹽酸鹽是製藥工業中常用以提升其溶解度的策略之一，罌粟鹼鹽酸鹽的生產通常會使用到大量的有機溶劑，且難以透過冷卻再結晶或反溶劑添加再結晶來製備。為了克服這個問題，在本研究中我們利用反應漿料結晶法製備罌粟鹼鹽酸鹽。自甲醇中再結晶的罌粟鹼鹽酸鹽的熔點為213℃，與購買的罌粟鹼鹽酸鹽的熔點224℃相比下降了11℃。 粉末X光繞射儀則顯示出其可能具有多晶型。除了反應漿料結晶法，我們還透過其他常規方法（即溶液結晶和無溶劑機械化學）製備鹽酸罌粟鹼，在反應漿料結晶法中， 0.12克的罌粟鹼先與0.5毫升異丙醇溶液混合形成漿料，再與0.12毫升、濃度為3M的鹽酸水溶液（罌粟鹼與鹽酸的摩爾比為1:1）在25℃下反應8小時，產率87.52 wt％（0.116克），並用傅立葉轉換紅外線光譜、粉末X光繞射儀和示差掃描量熱儀鑑定產物。為了控制罌粟鹼鹽酸鹽的粒徑分佈，在罌粟鹼與鹽酸的反應20分鐘後，進行溫度循環，並成功地控制了罌粟鹼鹽酸鹽的粒徑分佈，罌粟鹼鹽酸鹽的晶體尺寸分布從115微米到177微米，最終增加到420微米到470微米，晶貌則從粒狀顆粒變為棱柱形狀，透過示差掃描量熱儀證明在溫度循環後罌粟鹼全部轉化為罌粟鹼鹽酸鹽。最後，藉由將15毫升含有0.3克罌粟鹼鹽酸鹽的飽和水溶液與0.798毫升、濃度1M的氫氧化鈉水溶液（罌粟鹼鹽酸鹽與NaOH的摩爾比為1：1）在25℃下反應1小時，可以回收罌粟鹼，產率則為92.06wt％（0.25克），回收的罌粟鹼的結晶為針狀晶體。

Most of the drugs discovered, such as papaverine are poorly water soluble. Papaverine is an expensive drug, obtained from opium or complicated synthesis. Converting the free base into papaverine hydrochloride salt was one of the strategies used in pharmaceutical industry to increase the solubility of papaverine. Production of papaverine hydrochloride usually involved the use of a large amount of organic solvent. In addition, papaverine hydrochloride was difficult to recrystallize either by cooling or antisolvent addition. To overcome this problem, reaction slurry crystallization was chosen in this study to produce papaverine hydrochloride. The melting point of papaverine HCl salt recrystallized from methanol was 213oC, off by 11oC compared with the melting point of the purchased papaverine HCl salt at 225oC. The PXRD pattern indicated the possibility of polymorphism. Papaverine hydrochloride was also prepared by other conventional methods (i.e. solution crystallization and solventless mechanochemistry) with the goal of comparing with the one prepared through the intensified method (i.e. reaction slurry crystallization). Papaverine hydrochloride was synthesized through reaction slurry crystallization by reacting a slurry containing 0.12 g of papaverine and 0.5 mL of isopropyl alcohol slurry with 0.12 mL of 3M HCl having a molar ratio of papaverine to HCl of 1 to 1 at 25oC for 8 h. The solids were characterized by FT-IR, PXRD and DSC with a yield of 87.52 wt% (0.116 g). To control the particle size distribution of papaverine hydrochloride salt, after a 20 min reaction time for reaction slurry crystallization of papaverine HCl, temperature cycling was performed. The particle size distribution was successfully controlled. The crystal sizes of papaverine HCl increased from 115 to 177 μm to finally 420 to 470 μm. Crystals habits changed from grainy particles to finally prismatic shape. The conversion of papaverine free base to papaverine hydrochloride salt was eventually completed after temperature cycling as verified by DSC. Papaverine could be recovered by reacting 15 mL of water saturated with 0.3 g of papaverine hydrochloride with 0.798 mL of 1M NaOH having a molar ratio of papaverine hydrochloride to NaOH of 1 to 1 at 25oC for 1 h. The result was characterized by FT-IR, PXRD and DSC with a yield of 92.06 wt% (0.25 g). The crystal habits of recovered papaverine free base exhibited a needle crystal habit.

Chapter 1
(1) Halasz, A. S. Solubility as a Challenge in Drug Research and Development. In Solubility, Delivery and ADME Problems of Drugs and Drug-Candidates; Tihanyi, K.; Vastag, M.; Bentham Books: Hungary, 2011; pp 52-67.
(2) Waiver of in Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System: Guidance for Industry. https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm128219.htm (accessed April 30, 2018).
(3) Kalepu, S.; Nekkanti, V. Insoluble Drug Delivery Strategies: Review of Recent Advances and Business Prospects. Acta Pharm. Sin. B 2015, 5 (5), 442-453.
(4) Savjani, K. T.; Gajjar, A. K.; Savjani, J. K. Drug Solubility: Importance and Enhancement Techniques. ISRN Pharm. 2012, 2012, 1-10.
(5) 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.
(6) Patel, R. Parenteral Suspension: An Overview. Int J Curr Pharm Res 2010, 2 (3), 4-13.
(7) Patel, B. B.; Patel, J. K.; Chakraborty, S.; Shukla, D. Revealing Facts Behind Spray Dried Solid Dispersion Technology Used for Solubility Enhancement. Saudi Pharm. J. 2015, 23 (4), 352-365.
(8) Agrawal, Y.; Patel, V. Nanosuspension: An Approach to Enhance Solubility of Drugs. J. Adv. Pharm. Technol. Res. 2011, 2 (2), 81-88.
(9) A Solution for Poor Water Solubility. http://www.worldpharmaceuticals.net/features/featurea-solution-for-poor-water-solubility-4214373/ (accessed June 6, 2018).
(10) Gupta, S.; Kesarla, R.; Omri, A. Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems. ISRN Pharm. 2013, 1-16.
(11) Kakran, M.; Li, L.; Müller, R. H. Overcoming the Challenge of Poor Drug Solubility. Pharm. Eng. 2012, 32 (4), 1-7.
(12) Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.; Charman, W. N.; Pouton, C. W.; Porter, C. J. H. Strategies to Address Low Drug Solubility in Discovery and Development. Pharmacol. Rev. 2013, 65 (1), 315-499.
(13) Lee, T.; Wang, Y. W. Initial Salt Screening Procedures for Manufacturing Ibuprofen. Drug Dev. Ind. Pharm. 2009, 35 (5), 555-567.
(14) Derdour, L.; Reckamp, J. M.; Pink, C. Development of a Reactive Slurry Salt Crystallization to Improve Solid Properties and Process Performance and Scalability. Chem. Eng. Res. Des. 2017, 121, 207-218.
(15) Trask, A. V.; Haynes, D. A.; Motherwell, W. D. S.; Jones, W. Screening for Crystalline Salts via Mechanochemistry. Chem. Commun. 2005, 2006 (1), 51-53.
(16) Hasa, D.; Perissutti, B.; Cepek, C.; Bhardwaj, S.; Carlino, E.; Grassi, M.; Invernizzi, S.; Voinovich, D. Drug Salt Formation via Mechanochemistry: The Case Study of Vincamine. Mol. Pharm. 2013, 10 (1), 211-224.
(17) Lee, H. L.; Vasoya, J. M.; De Lima Cirqueira, M.; Yeh, K. L.; Lee, T.; Serajuddin, A. T. M. Continuous Preparation of 1:1 Haloperidol-Maleic Acid Salt by a Novel Solvent-Free Method Using a Twin Screw Melt Extruder. Mol. Pharm. 2017, 14 (4), 1278-1291.
(18) Clarke, B. J.; Hildebrand, R. P.; White, A. W. The Application of Salt Formation in the Chemistry and Technology of Hop Resins. J. Inst. Brew. 1976, 82, 212-217.
(19) Salt Selection in Drug Development. http://www.pharmtech.com/salt-selection-drug-development (accessed May 31, 2018).
(20) Wiedmann, T. S.; Naqwi, A. Pharmaceutical Salts: Theory, Use in Solid Dosage Forms and in Situ Preparation in an Aerosol. Asian J. Pharm. Sci. 2016, 11 (6), 722–734.
(21) Byrn, S. R.; Zografi, G.; Chen, X. Solid-State Properties of Pharmaceutical Materials; Wiley: U.S.A., 2017; pp 48-59.
(22) Makary, P. Principles of Salt Formation. UK J. Pharm. Biosci. 2014, 2 (4), 1-4.
(23) Guidance for Industry: New Chemical Entity Exclusivity Determinations for Certain Fixed- Combination Drug Products. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (accessed June 25, 2018).
(24) Serajuddin, A. T. M. Salt Formation to Improve Drug Solubility. Adv. Drug Deliv. Rev. 2007, 59 (7), 603-616.
(25) Monkhouse, D. C. Pharmaceutical Salts. J. Pharm. Sci. 1977, 66 (1), 1-19.
(26) Gao, Z.; Rohani, S.; Gong, J.; Wang, J. Recent Developments in the Crystallization Process: Toward the Pharmaceutical Industry. Engineering 2017, 3 (3), 343-353.
(27) He, Y.; Orton, E.; Yang, D. The Selection of a Pharmaceutical Salt-The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance. J. Pharm. Sci. 2018, 107 (1), 419-425.
(28) Paulekuhn, G. S.; Dressman, J. B.; Saal, C. Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database. J. Med. Chem. 2007, 50 (26), 6665-6672.
(29) Pudipeddi, M.; Serajuddin, A. T. M.; Grant, D. J. W.; Stahl, P. H. Solubility and Dissolution of Weak Acids, Bases, and Salts. In Handbook of Pharmaceutical Salts: Properties, Selection, and Use; Stahl, P. H.; Wermuth, C. G.; Freiburg: Germany, 2002; pp 19-40.
(30) Pindelska, E.; Sokal, A.; Kolodziejski, W. Pharmaceutical Cocrystals, Salts and Polymorphs: Advanced Characterization Techniques. Adv. Drug Deliv. Rev. 2017, 117, 111-146.
(31) Nechipadappu, S. K.; Ramachandran, J.; Shivalingegowda, N.; Lokanath, N. K.; Trivedi, D. R. Synthesis of Co-crystal/Salts of Flucytosine: Structural and Stability. New J. Chem. 2018, 42 (7), 5433-5446.
(32) 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.
(33) He, Y.; Ho, C.; Yang, D.; Chen, J.; Orton, E. Measurement and Accurate Interpretation of the Solubility of Pharmaceutical Salts. J. Pharm. Sci. 2017, 106 (5), 1190-1196.
(34) Wu, H.; West, A. R.; Vickers, M.; Apperley, D. C.; Jones, A. G. Synthesis, Crystallization and Characterization of Diastereomeric Salts Formed by Ephedrine and Malic Acid in Water. Chem. Eng. Sci. 2012, 77, 47-56.
(35) Tan, D.; Loots, L.; Friščić, T. Towards Medicinal Mechanochemistry: Evolution of Milling from Pharmaceutical Solid Form Screening to the Synthesis of Active Pharmaceutical Ingredients (APIs). Chem. Commun. 2016, 52 (50), 7760-7781.
(36) Wu, W.; Löbmann, K.; Rades, T.; Grohganz, H. On the Role of Salt Formation and Structural Similarity of Co-Formers in Co-Amorphous Drug Delivery Systems. Int. J. Pharm. 2018, 535 (1–2), 86-94.
(37) Hasa, D.; Perissutti, B.; Cepek, C.; Bhardwaj, S.; Carlino, E.; Grassi, M.; Invernizzi, S.; Voinovich, D. Drug Salt Formation via Mechanochemistry: The Case Study of Vincamine. Mol. Pharm. 2013, 10 (1), 211-224.
(38) Talapatra, S. K.; Talapatra, B. Chemistry of Plant Natural Products: Stereochemistry, Conformation, Synthesis, Biology, and Medicine; Springer: India, 2013: pp 802-809.
(39) Papaverine. www.drugfuture.com/chemdata/papaverine.html (accessed April 2, 2018).
(40) Aboutabl, E. A.; El-Azzouny, A. A.; Afifi, M. S. 1H-NMR Assay of Papaverine Hydrochloride and Formulations. Phytochem. Anal. 2002, 13 (6), 301-304.
(41) Bauer, V.; Čapek, R. Studies on the Neuropharmacology of Papaverine-I. The Curare-like Action Isolated Nerve-Muscle Preparation. Neuropharmacology 1971, 10 (4), 499-506.
(42) Al-Masri, I. M. Pancreatic Lipase Inhibition by Papaverine : Investigation by Simulated Molecular Docking and Subsequent In Vitro Evaluation. Jordan J. Pharm. Sci. 2013, 6 (3), 271-279.
(43) Ithakissions, S. D.; Tsatsas, G.; Nikokavouras, J.; Tsolis, A. Synthesis of Papaverine and Quinopavine Specifically Labelled with 14C. J. Labelled Compd. 1974, 10 (3), 369-379.
(44) Guthrie, D. A.; Frank, A. W.; Purves, C. B. Studies in the Polyoxyphenol Series: The Synthesis of Papaverine and Papaveraldine by the Pomeranz-Fritsch Method. Can. J. Chem. 1955, 33 (5), 729-742.
(45) Allen, I.; Buck, J. S. Papaverine: An Attempted Rugheimer Synthesis. J. Am. Chem. Soc. 1930, 52 (1), 310-314.
(46) Galat, A. Synthesis of Papaverine and Some Related Compounds. J. Am. Chem. Soc. 1951, 73 (8), 3654-3656.
(47) Han, X.; Lamshöft, M.; Grobe, N.; Ren, X.; Fist, A. J.; Kutchan, T. M.; Spiteller, M.; Zenk, M. H. The Biosynthesis of Papaverine Proceeds via (S)-Reticuline*. Phytochemistry 2010, 71 (11), 1305-1312.
(48) Patel, T. R.; Schoenwald, R. D.; Lach, J. L. Comparative Bioavailability of Papaverine Hydrochloride, Papaverine Hexametaphosphate and Papaverine Polymetaphosphate. Drug Dev. Ind. Pharm. 1981, 7 (3), 329–345.
(49) Littauer, M. D. D.; Wright, I. S. M. D. Papaverine Hydrochloride: Its Questionable Value as a Vasodilating Agent for Use in the Treatment of Peripheral Vascular Diseases. Am. Heart J. 1939, 17 (3), 325-333.
(50) Marciniec, B.; Kozak, M.; Naskrent, M.; Hofman, M.; Dettlaff, K.; Stawny, M. DSC and EPR Analysis of Some Radiation Sterilized Alkaloids. J. Therm. Anal. Calorim. 2010, 102 (1), 261-267.
(51) Roques, R.; Piquion, J.; Fourme, R.; Antré, D. Crystal and Molecular Structure of the Alkaloid Papaverine Hydrochloride. J. Cryst. Mol. Struct. 1973, 4 (4), 213-225.
(52) Datta, A. S.; Bagchi, S.; Chakrabortty, A.; Lahiri, S. C. Studies on the Weak Interactions and CT Complex Formations between Chloranilic Acid, 2,3-Dichloro-5,6-Dicyano-P-Benzoquinone, Tetracyanoethylene and Papaverine in Acetonitrile and Their Thermodynamic Properties, Theoretically, Spectrophotometrically Aided. Spectrochim. Acta - Part A Mol. Biomol. Spectrosc. 2015, 146, 119-128.

Chapter 2
(1) 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.
(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.
(3) Lee, T.; Wang, Y. W. Initial Salt Screening Procedures for Manufacturing Ibuprofen. Drug Dev. Ind. Pharm. 2009, 35 (5), 555–567.
(4) Derdour, L.; Reckamp, J. M.; Pink, C. Development of a Reactive Slurry Salt Crystallization to Improve Solid Properties and Process Performance and Scalability. Chem. Eng. Res. Des. 2017, 121, 207–218.
(5) Trask, A. V.; Haynes, D. A.; Motherwell, W. D. S.; Jones, W. Screening for Crystalline Salts via Mechanochemistry. Chem. Commun. 2006, (1), 51–53.
(6) Hasa, D.; Perissutti, B.; Cepek, C.; Bhardwaj, S.; Carlino, E.; Grassi, M.; Invernizzi, S.; Voinovich, D. Drug Salt Formation via Mechanochemistry: The Case Study of Vincamine. Mol. Pharm. 2013, 10 (1), 211–224.
(7) Wu, Z.; Yang, S.; Wu, W. Application of Temperature Cycling for Crystal Quality Control during Crystallization. CrystEngComm 2016, 18 (13), 2222–2238.

Chapter 3
(1) Grodowska, K.; Parczewski, A. Organic Solvents in the Pharmaceutical Industry. Acta Pol. Pharm. Res. 2010, 67 (1), 3–12.
(2) U.S. Food and Drug Administration. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (accessed May 29, 2018).
(3) Chemical Economic Handbook: Isopropyl Alcohol. https://ihsmarkit.com/products/isopropyl-alcohol-ipa-chemical-economics-handbook.html (accessed May 3, 2018).
(4) 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.
(5) Reus, M. A.; Deng, W. W. L. P.; Guguta, C.; Kramer, H. J. M.; Horst, J. H. Solubility: Importance , Measurements and Applications. White Paper: Technobis Crystallization System. 2016, p. 1–8.
(6) Marciniec, B.; Kozak, M.; Naskrent, M.; Hofman, M.; Dettlaff, K.; Stawny, M. DSC and EPR Analysis of Some Radiation Sterilized Alkaloids. J. Therm. Anal. Calorim. 2010, 102 (1), 261–267.
(7) Richardson, J.F.; Harker, J.H.; Backhurst, J.R. Chemical Engineering: Particle Technology and Separation Processes, 5th ed.; Butterworth Heinemann: New York, 1955.
(8) Galat, A. Synthesis of Papaverine and Some Related Compounds. J. Am. Chem. Soc. 1951, 73 (8), 3654–3656.
(9) Baizer, M. M.; Flushing, N. Y. Method for Producing Pure Papaverine Hydrochloride. US 2507135, May 9, 1950.
(10) Cozar, O.; Kiefer, W.; Lendl, B. Raman , IR , and Surface-Enhanced Raman Spectroscopy of Papaverine An Automated Setup for In Situ Synthesis of the Silver Substrate and Recording of the SER Spectra. 2004, 36, 47–55.
(11) Datta, A. S.; Chattaraj, S. B.; Chakrabortty, A.; Lahiri, S. C. Studies on the Weak Interactions and CT Complex Formations between Chloranilic Acid, 2,3-dicyano-p-benzoquinone, Tetracyanoethylene and Papaverine in Acetonitrile and Their Thermodynamic Properties, Theoretically, Spectrophotometrically Aided by FTIR. Spectrochim. ACTA PART A Mol. Biomol. Spectrosc. 2015, 146, 119–128.
(12) Macht, D. I.; Baltimore, M. D. A Pharmacologic and Clinical Study of Papaverin*. Arch Intern Med 1916, 19 (6), 786–805.
(13) Burger, A. The Benzylisoquinoline Alkaloids. In The Alkaloids: Chemistry and Physiology; Manske, R. H. F.; Holmes, H.L.; New York, 1954; Vol. 4; p. 29-45.
(14) Hifnawy, M. S.; Muhtadi, F.J. analytical Profile of Papaverine Hydrochloride. In Analytical Profiles of Drug Substances; Florey, K.; San Diego: California , 1994; Vol. 17; p. 367-448.
(15) Michalchuk, A. A. L.; Tumanov, I. A.; Konar, S.; Kimber, S. A. J.; Pulham, C. R.; Boldyreva, E. V. Challenges of Mechanochemistry: Is In Situ Real-Time Quantitative Phase Analysis Always Reliable? A Case Study of Organic Salt Formation. Adv. Sci. 2017, 4 (9), 1-7.
(16) Bag, P. P.; Ghosh, S.; Khan, H.; Devarapalli, R.; Malla Reddy, C. Drug–Drug Salt Forms of Ciprofloxacin with Diflunisal and Indoprofen. CrystEngComm 2014, 16 (32), 7393–7396.
(17) Hasa, D.; Perissutti, B.; Cepek, C.; Bhardwaj, S.; Carlino, E.; Grassi, M.; Invernizzi, S.; Voinovich, D. Drug Salt Formation via Mechanochemistry: The Case Study of Vincamine. Mol. Pharm. 2013, 10 (1), 211–224.
(18) Lee, H. L.; Vasoya, J. M.; De Lima Cirqueira, M.; Yeh, K. L.; Lee, T.; Serajuddin, A. T. M. Continuous Preparation of 1:1 Haloperidol-Maleic Acid Salt by a Novel Solvent-Free Method Using a Twin Screw Melt Extruder. Mol. Pharm. 2017, 14 (4), 1278–1291.
(19) Haser, A.; Cao, T.; Lubach, J. W.; Zhang, F. In Situ Salt Formation during Melt Extrusion for Improved Chemical Stability and Dissolution Performance of a Meloxicam-Copovidone Amorphous Solid Dispersion. Mol. Pharm. 2018, 15 (3), 1226–1237.
(20) Derdour, L.; Reckamp, J. M.; Pink, C. Development of a Reactive Slurry Salt Crystallization to Improve Solid Properties and Process Performance and Scalability. Chem. Eng. Res. Des. 2017, 121, 207–218.
(21) Pantelic, I.; Lukic, M.; Markovic, B.; Lusiana; Hoffmann, C.; Müller-Goymann, C.; Milic, J.; Daniels, R.; Savic, S. Development of a Prospective Isopropyl Alcohol-Loaded Pharmaceutical Base Using Simultaneous in Vitro/in Vivo Characterization Methods of Skin Performance. Drug Dev. Ind. Pharm. 2014, 40 (7), 960–971.
(22) Burlage, H. M.; Hawkins, D. B. Pharmaceutical Applications of Isopropyl Alcohol. I. As a Solvent in Pharmaceutical Manufacturing. J. Am. Pharm. Assoc. 1946, 35 (12), 379–384.
(23) Li, C. J. Reflection and Perspective on Green Chemistry Development for Chemical Synthesis-Daoist Insights. Green Chem. 2016, 18 (7), 1836–1838.
(24) Parente, E. Description and Identification. In Specification of Drug Substances and Products: Developmentand validation of Analytical Methods; Riley, C. M.; Rosanske, T. W.; Riley, S. R. R.; Waltham: USA, 2014; p. 91-106.
(25) Papaverine. www.drugfuture.com/chemdata/papaverine.html (accessed April 2, 2018).
(26) Wu, Z.; Yang, S.; Wu, W. Application of Temperature Cycling for Crystal Quality Control during Crystallization. CrystEngComm 2016, 18 (13), 2222–2238.
(27) Simone, E.; Klapwijk, A. R.; Wilson, C. C.; Nagy, Z. K. Investigation of the Evolution of Crystal Size and Shape during Temperature Cycling and in the Presence of a Polymeric Additive Using Combined Process Analytical Technologies. Cryst. Growth Des. 2017, 17 (4), 1695–1706.

Chapter 4
(1) Seetharaj, R.; Vandana, P. V.; Arya, P.; Mathew, S. Dependence of Solvents, pH, Molar Ratio and Temperature in Tuning Metal Organic Framework Architecture. Arab. J. Chem. 2015, 1–21.
(2) Kitamura, M.; Konno, H.; Yasui, A.; Masuoka, H. Controlling Factors and Mechanism of Reactive Crystallization of Calcium Carbonate Polymorphs from Calcium Hydroxide Suspensions. J. Cryst. Growth 2002, 236 (1), 323–332.
(3) Sawada, K. The Mechanisms of Crystallization and Transformation of Calcium Carbonates. Pure Appl. Chem. 1997, 69 (5), 921–928.
(4) Hixson, A. W.; Knox, K. L. Effect of Agitation on Rate of Growth of Single Crystals. Eng. Process Dev. 1951, 43 (9), 2144–2151.
(5) Harada, Y.; Kusada, K.; Sukenaga, S.; Yamamura, H.; Ueshima, Y.; Mizoguchi, T.; Saito, N.; Nakashima, K. Effects of Agitation and Morphology of Primary Crystalline Phase on Crystallization Behavior of CaO–SiO2–CaF2 Supercooled Melts. ISIJ Int. 2014, 54 (9), 2071–2076.