藥物的研究與發展是一個很費時與昂貴的過程。平均來說，一個新藥物從在實驗室研發到真正上市大約需要500到880百萬美元，而且整個過程需要約15年。在本論文中，最終的目標是要在藥物發展階段建立一套快速、便利和有系統的方法來改善效率以及節省時間和金錢。首先，我們建立了一個有關苯丁唑酮(phenylbutazone)結晶的資料庫。利用23種有機溶劑篩選的方式，有關苯丁唑酮溶解度(solubility)、同質異相(polymorphism)、結晶度(crystallinity)、晶貌(crystal habit)以及同質異相表的資料被完整收集。一種粗糙但簡單方便且只需要少量樣品的篩選方法也將在本論文中介紹給大家。同時，有關於苯丁唑酮新的同質異相，構形F，其結晶體是利用降溫的路徑個別在正丁醇(n-butyl alcohol)和苯甲醇(benzyl alcohol)的溶液裡所產生的。第二，苯丁唑酮的精益製造是利用球形結晶的方法在由同質異相表所推算出來的136組有機溶劑組合裡實行的。並且成功地提供了一組由乙腈(acetonitrile)、水(water)和正庚醇(n-heptane)的有機溶劑組合是具有最佳的產率、球形度和脆碎度來提供製藥業做為量產的依據。除此之外，利用球形結晶的方法，構形E是以一種跟文獻相較之下，更快速、簡單且省能源的方法製造出來。苯丁唑酮本身具有豐富的有關特性研究文獻以及不同的同質異構體，這就是我們選擇它當作我們的活性藥物成分（active pharmaceutical ingredient, API）的原因。但是本論文中的研究方法，可以用在其他的活性藥物成分、候選藥物或是簡單的有機分子上。

Drug discovery and development process was a long and expensive process. The average cost for a drug from laboratory to market was about USD 500 to USD 880 million and it takes ten to fifteen years to complete the whole process. In this thesis, the final target was to establish fast, convenient and systematic method to improve the efficiency, and money-saving for scale up in drug development stage. Firstly, a useful engineering data bank of solubility, polymorphism, crystallinity, crystal habit and Form Space by solvent screening for phenylbutazone would be established and a robust, miniature solvent screening method would be introduced. In the meantime, the new polymorph, Form F, was discovered in the crystals precipitated in n-butyl alcohol and benzyl alcohol by temperature cooling respectively. Secondly, the study of phenylbutazone in spherical crystallization for lean solid manufacturing was carried out through 136 solvent combinations derived from the Form Space. A successful solvent combination giving the best yield, sphericity, and friability for scale-up in the pharmaceutical industry was acetonitrile-water-n-heptane. Besides, with spherical crystallization, Form E was produced in a fast, energy saving and easy way compared with literatures. Phenylbutazone was chosen as the active pharmaceutical ingredient (API) because of the abundance in literatures about the characterization of phenylbutazone and its polymorphs. By the initial solvent screening methods in this thesis could also be applied to some other APIs or drug candidates or simple organic materials.

References
1 C. Han, and B. Wang, “Factors that impact the developability of drug candidates: an overview,” Chapter 1 in Drug delivery: principles and applications, edited by B. Wang, T. Siahaan, and R. Soltero, (John Wiley & Sons, 2005) pp. 1-5.
2 K. Sweeny, “Technology trends in drug discovery and development: implications for the development of the pharmaceutical industry in Australia”, draft working paper No. 3, pharmaceutical industry project, CSES, Victoria University, Melbourne.
3 M. S. Lipsky, and L. K. sharp, “From idea to market: the drug approval process,” JABFP, 14(5), 326-367 (2001).
4 S. Kraljevic, P. J. Stambrook, and K. Pavelic, “Acceleration drug discovery,” EMBP reports, 5(9), 837-842 (2004).
5 G. W. Galdwell, “Compound optimization in early- and late-phase drug discovery: acceptable pharmacokinectic properties utilizing combined phtsicochemical, in vitro and in vivo screens,” Cut. Opin. Drug Disc. Dev., 3(1), 30-41 (2000).
6 L. Yu, S. M. Reutzel, and G. A. Stephen, “Physical characterization of polymorphic drugs: an integrated characterization strategy.” PSTT, 1(3), 118-127 (1998).
7 Y. Yoswhihashi, E. Yonemochi and K. Terada, “Estimation of initial dissolution rate of drug substance by thermal analysis: application for carbamazepine hydrate.” Pharm. Devel. Tech.,
7(1), 89-95 (2002).
8 D. J. W. Grant, “Theory and origin of polymorphism,” Chapter 1 in Polymorphism in pharmaceutical solids, Edited by H.G. Brittain, (Marcel Dekker, INC. New York, 1999) pp. 1-33.
9 L. X. Yu, M. S. Furness, A. Raw, K. P. W. Outlaw, N. E. Nashed, E. Ramos, S. P. F. Miller, R. C. Adams, F. Fang, R. M. Patel, F. O. Holcombe, Jr., Y. Y. Chiu, and A. S. Hussain, “Scientific considerations of pharmaceutical solid polymorphism in abbreviated new drug applications,” Pharm. Res., 20(4), 531-536 (2003).
10 T. L. Threlfall, “ Analysis of organic polymorphs a review,” Analyst., 120(10), 2435-2459 (1995).
11 M. Fujiwara, Z. K. Nagy, J. W. Chew, and R. D. Braatz, “First-priciples and direct design approaches for the control of pharmaceutical crystallization,” J. Process. Control., 15(5), 493-504 (2005).
12 N. A. Lewis, “A tracking tool for lean solid-dose manufacturing,” Pharm. Tech., 30(10), 94-108 (2006).
13 A. Kadir, B. H. Ali, G. A. Hadrami, A. K. Bashir, M. F. Landoni, and P. Lees, “Phenylbutazone pharmacokinetics and bioavailability in the dromedary camel (camelus dromedarius),” J. Vet. Pharmacol. Therap., 20(1), 54-60 (1997).
12
14 M. D. Tuladhar, J. E. Carles, and M. P. Summers, “Thermal behavior and dissolution properties of phenylbutazone polymorphs,” J. Pharm. Pharmacol., 35(4): 208-214 (1983).
15 H. G. Ibahim , F. Pisano, and A. Bruno, “Polymorphism of penylbutazone: properties and compressional behavior of crystals,” J. Pharm. Sci., 66(5), 669-673 (1977).
16 N. Kaneniwa, J. Ichikawa, and T. Matsumoto, “ Preparation of phenylbutazone polymorphs and their transformation in solution,” Chem. Pharm. Bull., 36(3) 1063-1073 (1988).
17 H. H. Paradies, “Structure of phenylbutazone and mofebutazone in the crystalline state and in solution,” J. Pharm. Sci., 76(12), 919-929 (1987).
18 S. Datta, and D. J. W. Grant, “Computing the relative nucleation rate of phenylbutazone and sulfamerazine in various solvents,” Cryst. Growth Des., 5(4), 1351-1357 (2005).
19 T. Hosokawa, S. Datta, A. R. Sheth, and D. J. W. Grant, “Relationship between crystal structures and thermodynamic properties of phenylbutazone solvates,” Cryst. Eng. Comm, 6(44), 243-249 (2004).
20 N. G. Anderson, “Solvent selection,” Chapter 4 in Practical Process Research & Development (Academic Press, New York, 2000) pp. 81-111.
21 T. Lee, C. S. Kuo, and Y. H. Chen, “Solubility, polymorphism, crystallinity, and crystal habit of acetaminophen and ibuprofen by initial solvent screening,” Pharm. Tech., 30(10), 72-92 (2006).
13
22 T. Lee, and F. B. Hsu, “A cross-performance relationship between carr’s index and dissolution rate constant: the study of acetaminophen batches,” Drug Dev. Ind. Pharm., 33(11), 1273-1284 (2007).
23 T. Lee, H. J. Hou, H. Y. Hsieh, Y. C. Su, Y. W. Wang, and F. B. Hsu, “The prediction of the dissolution Rate constant by mixing rules: the study of acetaminophen batches,” Drug Dev. Ind. Pharm., 34(5), 522-535 (2008).
24 Á. Beretzky, P. Kása Jr., K. Pintye-Hódi, J. Bajdik, P. Szabó-Révész, and I. Erõs, “Pelletization of needle-shaped phenylbutazone crystals,” J. Therm. Anal. Calorim., 69(2), 525-539 (2002).
25 A. Nokhodchi, M. Maghsoodi, D. Hassan-Zadeh, and M. Barzegar-Jalali, “Preparation of agglomerated crystals for improving flowability and compactibility of poorly flowable and compactible drugs and excipients,” Powder Tech., 175(2), 73-81 (2007).
26 T. Threlfal, “Crystallizatopn of polymorphs: thermodynamic insight into the role of solvent,” Org. Process Res. Dev., 4(5), 384-390 (2000).
1 D. J. W. G.rant, “Theory and origin of polymorphism,” Chapter 1 in Polymorphism in pharmaceutical solids, edited by H. G. Brittain, (Marcel Dekker, Inc., New York, 1999) pp. 1-21.
2 T. L. Threlfall, “Analysis of organic polymorphs: a review,” Analyst, 120(10), 2435-2460 (1995).
3 V. Koradia, G. Chawla, and A. K. Bansal, “Qualitive and quantitative analysis of clopidogrel bisulphate polymorphs,” Acta Pharm. 54(3), 193-204 (2004)
4 T. Hosokawa, S.Datta, A. R. Sheth and D. J. W. Grant, “Relationships between crystal structures and thermodynamic properties of phenylbutazone solvates,” Cryst. Eng. Comm. 6(44), 243-249 (2004).
5 G. Chawala, and A. K. Bansal, “Challenges in polymorphism of pharmaceuticals,” CRIPS 5(1), 9-12 (2004).
6 S. Mirza, I. Miroshnyk, J. Heinamaki, L. Christiansen, M. Karjalainen, and J. Yliruusi, “Influence of solvents on the variety of crystalline forms of erythromycin,” AAPS Pharm. Sci. 5(3), 1-9 (2003).
7 P. Di Martino, A-M. Guyot-Hermann, P. Conflant, M. Drache, and J-C. Guyot, “A new pure paracetmol for direct compression: the orthorhombic form,” Int. J. Pharm., 128(1-2), 1-8 (1996).
8 L. Yu, S. M. Reutzel, and G.. A. Stephenson, “Physical characterization of polymorphic drugs: an integrated characterization strategy,” PSTT, 1(3), 118-127 (1998).
9 N. V. Phadnis , R. K. Cavatur, and R. Suryanarayanan, “Identification of drugs in pharmaceutical dosage forms by X-ray powder diffractometry,” J Pharm Biomed Anal., 15(7), 929-943 (1997).
10 G. Nichols, and C. S. Frampton, “Physicochemical characterization of the orthorhombic polymorph of paracetamol crystallized from solution,” J. Pharm. Sci., 87(6), 684-693 (1998).
11 E. V. Boldyerva, V. A. Drebushchak, I. E. Paukov, Y. A. Kovalevskaya, and T. N. Drebushchak, “DSC and adiabatic calorimetry study of the polymorphs of paracetamol,” J. of Them. Anal. Calor., 77(2), 607-623 (2004).
12 D. Giron, “Thermal analysis and calorimetric methods in the characterization of polymorphs and solvate,” Thermochim. Acta, 248(1), 1-59 (1995).
13 B. R. Spong, C. P. Price, A. Jayasankar, A. J. Matzger, and N. R. Horndo, “General principles of pharmaceutical solid polymorphism a supramolecular perspective,” Adv. Drug Del. Rev., 56(3), 241-274 (2004).
14 G. W. Smith, “Precipitation kinetics in an air-cooled aluminum alloy: a composition of scaning and isothermal calorimetry measurement methods,” Thermochim. Acta, 313(1), 27-36 (1998).
33
15 T. Hatakeyama, and Z. Liu, “Conformation of TA apparatus,” Chapter 2 in Handbook of thermal analysis, 1st edition, (John Wiley & Sons, Baffins Lane, England, 1998) pp. 17-19.
16 K. L. A. Chan, and S. G. Kazarian, “Fourier transform infrared imaging for high-throughput analysis of pharmaceutical formulation,” J. Comb. Chem.,
7(2), 185-189 (2005).
17 N. S. Murthy, and F. Reidinger, “X-ray analysis,” Chapter 7 in Matericals characterization and chemical analysis, (J. P. Sibilia, Wiley-Vch , New York, USA, 1996) pp. 143-149.
18 M. Davidovich, J. Dimarco, J. Z. Gougoutas, R. P. Scaringe, I. Vitez, S. Yin, “Detection of polymorphic artifacts in powder x-ray diffraction determination,” Am. Pharm. Rev., 138 (1), 1-2 (1996).
19 J. E. Macur, J. Marti, and S. C. Lui, “Microscopy,” Chapter 8 in Matericals characterization and chemical analysis, , 2nd edition, (J. P. Sibilia, Wiley-Vch, New York, USA, 1996) pp. 167-177.
20 K. Gotoh, H. Masuda, and K. Higashitani, “Powder-handling operation,” Chapter 5 in Powder technology handbook, 2nd edition, (Marcel Dekker, Inc, New York, 1997) pp. 413-730
References
1 B. Shekunov, and P. York,“Crystallization processes in pharmaceutical technology and drug delivery design,” J. Crystal Growth, 211(1), 122–136 (2000).
2 D. J. W. Grant, “Theory and origin of polymorphism,” Chapter 1 in Polymorphism in pharmaceutical solids, edited by H. G. Brittain, (Marcel Dekker, INC., New York, 1999) pp. 1-21.
3 C. U. Yurteri, M. K. Mazumder, N. Grable, G. Ahuja, S. Trigwell, A. S. Biris, R. Sharma, and R. A. Sims, “Electrostatic effects on dispersion, transport, and deposition of fine pharmaceutical powders: development of an experiment method for quantitative analysis,” Particulate Sci. Tech. 20(1), 59-79 (2002).
4 M. E. Möbius, B. E. Lauderdale, S. R. Nagel, and H. M. Jaeger, “Brazail-nut effect: size separation of granular particles,” Nature 414, 270 (2001).
5 G. K. Bolhuis, and Z. T. Chowhan, “Material for direct compaction,” in Pharmaceutical Powder Compaction Technology, G. ALderborn and C. Nystrom, Eds. (Marcel Dekker, New York, NY, 1996), Ch. 14, pp. 419-500.
6 M. D. Tousey, “The granulation process 101: basic technologies for tablet marking,” Pharm. Technol. 26 (Tableting and Granulation), 8-13 (2002).
7 G. W. Gereg, and M. L. Coppola, “Roller compaction feasibility studies for new drug candidates-laboratory to production scale,” Pharm.Technol., 26 (Tableting and Granulation),
14-23 (2002).
8 P. York “Solid-state properties of powders in the formulation and processing of solid dosage forms.” Int. J. Pharm., 14(1), 1-28 (1983).
9 P. V. Marshal, and P. York, “Crystallization solvent induced solid-state and particulate modifications of nitrofurantoin,” Int. J. Pharm., 55(2-3), 257-263 (1989).
10 A. Florence, and D. Attwood, “Physicochemical principles of pharmacy,” 3rd ed. (Macmillan Press, London, 1998) pp. 5-35.
11 D. J. W. Grant, “Approaches to polymorphism screening,” chapter 11 in Polymorphism in pharmaceutical solids, edited by H. G. Brittain, ( Marcel Dekker, INC., New York, 1999) p. 289.
12 W. Beckman, W. Otto, and W. Budde, “Crystallisation of the stable polymorph of hydroxytriendione: seeding process and effects of purity,” Org. Proc. Res. Dev., 5 ( 4 ), 387-392 (2001).
13 R. Hilfiker, J. Berghausen, F. Blatter, A. Burkhard, S. M. D. Paul, B. Freiermuth, A. Geoffroy, U. Hofmeier, C. Marcolli, B. Siebenhaar, M. Szelagiewicz, A. Vit, and M. V. Raumer, “Polymorphism-integrated approach from high-throughput screening to crystallization optimization,” J. Therm. Anal. Calorim., 73(2), 429-440 (2003).
87
14 A. Kadir, B. H. Ali, G. A. Hadrami, A. K. Bashir, M. F. Landoni, and P. Lees, “Phenylbutazone pharmacokinetics and bioavailability in the dromedary camel (camelus dromedarius),” J. Vet. Pharmacol. Therap., 20(1), 54-60 (1997).
15 H. H. Paradies, “Structure of phenylbutazone and mofebutazone in the crystalline state and in solution,” J. Pharm. Sci., 76(12), 919-929 (1987).
16 S. N. Bhattachar, L. A. Deschenesa, and J. A. Wesleya, “Solubility: it is not just for physical chemists,” Drug Discovery Today, 11(21-22), 1012-1018 (2006)
17 J. W. Mullin, “solution and solubility,” Chapter 3 in Crystallization, 3rd edition, (Butterworth-Heinemann, London, 1992), p. 82
18 C. J. Price, “Take some solid steps to improve crystallization,” Chem. Eng. Prog., 93(9), 34-43 (1997).
19 K. Srinivasan, S. Anbukumar, and P. Ramasamy, “Mutual solubility and metastable zone width of NH4H2PO4-KHAPO4 mixed solutions and growth of mixed crystals,” J. Cryst. Growth, 151(1), 226-229 (1995).
20 J. Berstein, R. J. Davey, and J-O. Henck, “Concomitant polymorphs,” Angew.
Chem. Int. Ed. 38(23), 3440-3461 (1999).
21 D. Giron, “Thermal analysis and calorimetric methods in the characterization of polymorphs and solvates,” Thermochim. Acta, 248(1), 1-59 (1995).
88
22 R. J. Behme, and D. Brooke, “Heat of fusion measurement of a low melting polymorph of carbamazepine that undergoes multiple-phase changes during differential scanning calorimetry analysis,” J. Pharm. Sci., 80(10), 986-990 (1991).
23 T. Threlfall, “Crystallization of polymorph: thermodynamic in sight into the role of solvent,” Org. Process Res. Dev., 4(5), 384-390 (2000)
24 M. Charoenchaitrakool, F. Dehghani, and N. R. Foster, “Micronization by rapid expansion of supercritical solutions to enhance the dissolution rates of poorly water-soluble pharmaceuticals.” Ind. Eng. Chem. Res., 39 (12), 4794 -4802 (2000).
25 A. Florence, and D. Attwood, “Physicochemical principles of pharmacy,” 3rd edition (Macmillan Press Ltd., London, 1998) pp. 5-35.
26 J. W. Mullin, “Solution and solubility,” Chapter 3 in Crystallization, 3rd edition, (Butterworth-Heinemann, London, 1992) p.248.
27 M. Lahav, and L. Leiserowitz, “The effect of solvent on crystal growth and morphology”, Chem. Eng. Sci., 56(7), 2245-2253 (2001).
28 C. Stoica, P. Verwer. H. Meekes, P. J. C. M. van Hoof, F.M. Kaspersen, and E. Vlieg, “Understanding the effect of a solvent on the crystal habit,” Cryst. Growth Des., 4(4), 765-768 (2004).
89
29 N. Rasenack, and B. W. Muller, “Crystal habit and tableting behavior,” Int. J. Pharm., 244(1-2), 45-57 (2002).
30 A. K. Tiwary, “Modification of crystal habit and its role in dosage form performance,” Drug Dev. Ind. Pharm., 27(7), 699-709 (2001).
31 A. F. M. Barton, “Handbook of solubility parameters and other cohesion parameter,” 2nd edition, (CRC Press, USA, 1991) pp.69-149.
32 T. Lee, Y. H. Chen, and C. W. Zhang. (2007). Solubility, polymorphism, crystallinity, crystal habit, and drying scheme of (R, S)-(±)-sodium ibuprofen dihydrate. Pharm. Tech., 31(6), 72-87.
33 M. D. Tuladhar, J. E. Carles, and M. P. Summers, “Thermal behavior and dissolution properties of phenylbutazone polymorphs,” J. Pharm. Pharmacol., 35: 208-214 (1983).
34 N. G. Anderson, Practical Process Research & Development (Academic Press, New York, NY, 2000), pp. 81-111.
35 T. Lee, C. S. Kuo, and Y. H. Chen., “Solubility, polymorphism, crystallinity, and crystal habit of acetaminophen and ibuprofen by initial solvent screening,” Pharm. Tech., 30(10), 72-92 (2006).
36 H. G. Ibahim, F. Pisano, and A. Bruno, “Polymorphism of phenylbutazone: properties and
90
compressional behavior of crystals,” J. Pharm. Sci., 66(5), 669-673 (1977).
37 N. Kaneniwa, J. Ichikawa, and T. Matsumoto, “Preparation of phenylbutazone polymorphs and their transformation in solution,” Chem. Pharm. Bull., 36(3) 1063-1073 (1988).
38 T. Hosokawa, S. Datta, A. R. Sheth, and D. J. W. Grant, “Relationship between crystal structures and thermodynamic properties of phenylbutazone solvates,” Cryst. Eng. Comm, 6(44), 243-249 (2004).
39 T. Hosokawa, S. Datta, A. R. Sheth, N. R. Brooks, V. G. Young, and D. J. W. Grant, “Isostructurality among five solvates of phenylbutazone,” Cryst. Growth Des., 4(6), 1195-1201 (2004).
References
1 M. Asada, H. Takahashi, H. Okamoto, H. Tanino, and K. Danjo, “Theophylline particle design using chitison by spray drying,” Int. J. Pharm. 270(1-2), 167-174 (2004).
2 J. Straatsma, G.. V. Houwelingen, and A. E. Steenbergen, “Spray drying of food products: 1. Simulation model,” J. Food Eng. 42(2), 67-72 (1999).
3 J. Katta, and A. C. Rasmuson, “Spherical crystallization of benzoic acid,” Int. J. Pharmaceut., 348(1-2), 61-69 (2008).
4 S. Bhadra, and M. Kumar, Sunil Jain, S. Agrawal, and G. P. Agrawal, “Spherical crystallization of mefenamic acid,” Pharm. Tech., 28(1), 66-76 (2004).
5 A. Nokhodchi, M. Maghsoodi, D. Hassan-Zadeh, and M. Barzegar-Jalali, “Preparation of agglomerated crystals for improving flowability and compactibility of poorly flowable and compactible drugs and excipients,” Powder Tech., 175(2), 73-81 (2007).
6 K. I. Popov, S. Krsti, M. Obradovi, M. G. Pavlovi, L. Pavlovi, and V. Ivanovi, “The effect of the particle shape and structure on the flowability of electrolytic copper powder.I. Modeling of a representative powder particle,” J. Serb. Chem. Soc., 68(10), 771–777 (2003)
7 Y. Kawashima, M. Imai, H. Takeuchi, H. Yamamoto, K. Kamiya, and T. Hino, “Improved flowability and compactibility of spherically agglomerated crystals of ascorbic acid for direct
for direct tableting designed by spherical crystallization process,” Powder Tech., 130 (1), 283-289 (2003).
8 H. Goczo, P. S. Revesz, B. Farkas, M. Hasznos-Nezdei, S. F. Serwanis, K. Pinyye-Hodi, P. Kasa, Jr., I. S. Eros, I. Antal, and S. Marton, “Development of spherical crystals of acetylsalicylic acid for direct tablet-making,” Chem. Pharm. Bull., 48(12), 1877-1881 (2000).
9 A. S. Utada, L. Y. Chu, A. Fernandez-Nieves, D. R. Link, C. Holtze, and D. A. Weitz, “Dripping, jetting, drops, and wetting: the magic of microfluics,” MRS BULLETIN, 32, 702-708 (2007).
10 U. Teipel, T. Heintz, and H. H. Krause, “Crystallization of spherical ammonium dinitramide (AND) particles,” Propellant, Explosives, Pyrotechnics, 25(8), 81-85 (2000).
11 A. R. Paradkar, K. R. Mahadik, and A. P. Pawar, “Spherical crystallization a novel particle design technique,” Indian Drug, 31(6), 283-299 (1998).
12 Y. Kawashima, H.Takeuchi, T. Niwa, and T. Hino, “The development of a novel emulsion-solvent-diffusion preparation method of agglomerated crystals for direct tableting and evaluation of their compressibilities,” J. Soc. Powder Tchnol. Japan, 26, 659-665 (1989).
13 D. Amaro-González, and B. Biscans, “Spherical agglomeration during crystallization of an active pharmaceutical ingredient,” Powder Tech., 128(2), 188-194 (2002).
129
14 A. Sano, T. Kuriki, Y. Kawashima, H. Takeuchi, and T. Niwa, “Particle design of tolbutamide by spherical crystallization technique. II. Factors causing polymoepism of tolbutamide spherical agglomerates,” Chem. Pharm. Bull., 37(8), 2183-2187 (1989).
15 Y. Kawashima, M. Okumura, and H. Takenake, “Spherical crystallization: direct spherical agglomeration of salicylic acid crystals during crystallization,” Science, 216(4550), 1127-1128 (1982).
16 K. Morishima, Y. Kawashima, and H. Takeuchi, “Micromeritic characteristics and agglomeration mechanisms in the spherical crystallization of bucillamine by the spherical agglomeration and the emulsion solvent diffusion methods,” Powder Technol., 76(1), 57-64 (1993).
17 K. Kachrimanis, I. Nikolakakis, and S. Malamataris, “Spherical crystal agglomeration of ibuprofen by the solvent-change technique in presence of methacrylic polymers,” J. Pharm. Sci., 89(2), 250-259 (2000).
18 A. Ribardière, P. Tchoreloff, G. Couarraze, and F. Puisieux, “Modification of ketoprofen bead structure produced by the spherical crystallization technique with a two-solvent system,” Int. J. Pharm., 144(2), 195-207 (1996).
19 Y. Kawashima, T. Niwa, H. Takeuchi, T. Hino, Y. Itoh, and S. Furuyama, “Characterization of polymorph of tranilast anhydrate and tranilast monohydrate when crystallized by two solvent change spherical crystallization techniques,” J. Pharm. Sci., 80(5), 472-478 (1991).
130
20 Y. Kawashima, S. Aoki, H. Takenaka, and Y. Miyake, “Preparation of spherically agglomerated crystals of aminophylline,” J. Pharm. Sci., 73(10), 1407-1410 (1984).
21 Y. Kawashima, S. Y. Lin, M. Naito, and H. Takenaka, “Direct agglomeration of sodium theophylline crystals produced by salting out in liquid,” Chen. Pharm. Bull., 30(5), 1837-1843 (1981).
22 Y. Kawashima, M. Okumura, and H. Takenaka, “The effect of temperature on the spherical crystallization of salicylic acid,” Powder Technol., 39(1), 41-47 (1984).
23 A. Sano, T. Kuriki, Y. Kawashima, H. Takeuchi, T. Hino, and T. Niwa, “Particle design of tolbutamide by spherical crystallization technique. III. Micrometric properties and dissolution rate of tobutamide spherical agglomerates prepared by the quasi-emulsion solvent diffusion method and the solvent change method,” Chem. Pharm. Bull., 38(3), 733-739 (1990).
24 H. L. Chow, and W. M. Leng, “A study of the mechanisms of wet spherical agglomeration of pharmaceutical powders,” Drug Dev. Ind. Pharm., 22(4). 357-371 (1996).
25 M. Jbilou, A. Ettabia, A. M. Guyot-Hermann, and J. C. Guyot, “Ibuprofen agglomerates preparation by phase separation,” Drug Dev. Ind. Pharm., 25(3), 297-305 (1999).
26 P. D. Martino, C. Barthelemy, F. Piva, E, Joiris, G. F. Palmieri, and S. Martelli, “ Improved dissolution behavior of fenbufen by spherical crystallization,” Drug Dev. Ind. Pharm., 25(10), 1073-1081 (1999).
131
27 M. Nocent, L. Bertocchi, F. Espitalier, M. Baron, and G. Couarraze, “Definition of a solvent system for spherical crystallization of salbutamol sulfate by quasi-emulsion solvent diffusion (QESD) Method,” J. Pharm. Sci., 90(10), 1620-1627.
28 A. R. Paradkar, A. P. Pawar, J. K. Chordiya, V. B. Patil, and A. R. Ketkar, “Spherical crystallization of celecoxib,” Drug Dev. Ind. Pharm. 28(10), 1213-1220 (2002).
29 A. P. Pawar, A. R. Paradkar, S. S. Kadam, and K. R. M.ahadik, “Crystallo-co-agglomeration: a novel to obtain ibuprofen-paracetamol agglomerates,” AAPS Pharm. Sci. Tech., 5(3), 1-7 (2004).
30 Á. Beretzky, P. Kása Jr.,K. Pintye-Hódi, J. Bajdik, P. Szabó-Révész, and I. Erõs, “Pelletization of needle-shaped phenylbutazone crystals,” J. Therm. Anal. Calorim., 69(2), 525-539 (2002).
31 H. H. Paradies, “Structure of phenylbutazone and mofebutazone in the crystalline state and in solution,” J. Pharm. Sci., 76(12), 919-929 (1987).
32 M. D. Tuladhar, J. E. Carless, and M. P. Summer, “Thermal behavior and dissolution properties of phenylbutazone polymorphs,” J. Pharm. Pharmacol., 35(4), 208-214 (1983).
33 H. G. Ibahim, F. Pisano, and A. Bruno, “Polymorphism of phenylbutazone: properties and compressional behavior of crystals,” J. Pharm. Sci., 66(5), 669-673 (1977).
34 T. Lee, and S. T. Hung, “Cocktail-solvent screening to enhance solubility, increase crystal
132
yield, and induce polymorph,” Pharm. Tech., 32(1), 76-95 (2008).
35 W. Beckmann, “Seeding the desired polymorph: background, possibilities, limitations, and case studies,” Org. Proc. Res. Dev., 4(5), 372-383 (2000).
36 N. G. Anderson, Practical Process Research & Development (Academic Press, New York, NY, 2000), pp. 81-111.
37 D. J. C. Constable, C. Jimenez-Gonzalez, and R. K. Henderson, “Perspective on solvent use in the pharmaceutical industry,” Org. Process Res. Dev., 11(1), 133-137 (2007).
38 K. J. Kim, and A. Mersmann, “Estimation of meta-stable zone width in different nucleation processes,” Chem. Eng. Sci., 56 (7), 2315-2324 (2001).
39 A. Y. Huang, and J. C. Berg, “Gelation of liquid bridges in spherical agglomeration,” Colloids Surf., A, 215(1-3), 241-252 (2003).
40 N. Kaneniwa, J. Ichikawa, and T. Matsumoto, “Preparation of phenylbutazone polymorphs and their transformation in solution,” Chem. Pharm. Bull., 36(3), 1063-1073 (1988).
41 Y. Matsuda, S. Kawaguchi, H. Kobayashi, and J. Nishijo, “Physicochemical characterization of spray-dried phenylbutazone polymorphs,” J. Pharm. Sci., 73(2), 173-179 (1984).
Reference
1 Y. Matsuda, S. Kawaguchi, H. Kobayashi, and J. Nishijo, “Physicochemical characterization of spray-dried phenylbutazone polymorphs,” J. Pharm. Sci., 73(2), 173-179 (1984).