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Hsiang Yu Hsieh is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.
Yan Chan Su is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.
Hung Ju Hou is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.
The authors describe the importance of a rapid and an abbreviated screening strategy by initial solvent screening in 20-mL scintillation vials.
Many recent important solvent-based processes such as spherical crystallization, the spreading of cube-shaped particles, monodispersed double emulsions, microemulsions, and organic nanocrystal fabrication, involve combinations of two or three solvents (1–26). However, to the authors' knowledge, no literature has laid out a systematic way to identify the best solvent combinations, even though the composition ratio of the solution at the time of nucleation profoundly determines the solubility, polymorphism, and crystal habits of organic compounds functioning as in the case of the active pharmaceutical ingredients (APIs) (7, 8, 27).
(NICHOLAS RIGG/GETTY IMAGES)
This article will re-emphasize the importance of a rapid and abbreviated screening strategy by initial solvent screening in 20-mL scintillation vials. The screen provides engineering information in solubility curves, solubility spheres, polymorphs, crystallinity, form spaces (also known as solvent miscibility plots), and crystal habits of a given compound for solvent-based processes (see Figure 1) (28–31). The attractiveness of this strategy is its ability to be adopted or automated by common laboratories with only a small amount of chemical compounds. The probable solvent combinations of a good solvent, an antisolvent, and a bridging liquid for solvent-based processes are summarized systematically in the form space and can be graphically deduced.
Figure 1: Initial solvent screening in a 20-mL scintillation vial provides engineering information about (counterclockwise from top) solubility curves, polymorphism, solubility spheres, crystal habits, and form space for solvent-based processes. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
Initial solvent screening was thoroughly tested using three model APIs: carbamazepine (5H-dibenze[b,f]azepine-5-carboxamide), an anticonvulsant used to treat epilepsy and trigeminal neuralgia (see Figure 2a); cimetidine (N"-cyano-N-methyl-N'-[2-[[5-methyl-1H-imidazol-4-yl]methyl]thio]-ethyl]-guanidine), a specific competitive histamine H2-receptor antagonist used in the treatment of human peptic ulcers (see Figure 2b); and phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione), a nonsteroidal anti-inflammatory drug with antipyretic and analgesic activity (see Figure 2c). These compounds were studied because of their commercial value; their abundant characterization information in the literature (see Table Ia–c); the lack of extensive solvent studies on their solubility, polymorphism, crystallinity, and crystal habits; and the variety of their naturally occurring polymorphs, hydrates, and solvates (see Figure 3) (32–69).
Figure 2: Molecular structures of (a) carbamazepine (5H-dibenze[b,f]azepine-5-carboxamide), (b) cimetidine (N"-cyano-N-methyl-N'-[2-[[5-methyl-1H-imidazol-4-yl]methyl]thio]-ethyl]-guanidine), and (c) phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione).
Although carbamazepine has numerous polymorphs and solvates, it has four main polymorphs and two hydrates: Forms I–IV, and Dihydrates I and II (36, 43, 44). Forms I–III are enantiotropic with respect to each other (34, 36). The stability of carbamazepine is in the order of Form III, Form I, Form IV, Form II, based on the density rule, and the initial dissolution rate of carbamazepine is in the order of Form III, Form I, Dihydrate III (38, 43). Cimetidine has four polymorphs and three monohydrates: Forms A–D, and Monohydrates 1–3 (53). Forms A–D are monotropic (57). Although Forms A and D are virtually isoenergetic crystals, the stability of Form D is slightly higher than that of Form A (58). The solubility of Form A is greater than that of Form B, and Form C (54). Phenylbutazone has six polymorphs and six solvates: Forms α, β, γ, δ, ε, and ζ, and phenylbutazone 2:1 solvates with benzene, cyclohexane, 1,4-dioxane, tetrahydrofuran, tetrachloromethane, and chloroform (62, 63, 65, 69). Forms β and δ are monotropic. Forms α and β, and Forms α and δ are enantiotropic (66).
Table Ia: Characterization methods for four polymorphs and two dihydrates of carbamazepine.
Materials and methods
APIs. Carbamazepine, white crystalline prismatic powders (C15H12N2O, MW: 236.67 g/mol, melting point (mp) = 191–192 °C, reagent grade, Lot: 036k1219) and cimetidine, white crystalline rodlike powders (C10H16N6S, MW: 252.34 g/mol, mp = 141–143 °C, reagent grade, Lot: 088H1317) were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. Phenylbutazone, white crystalline needle-shaped powders (C19H20N2O2, MW: 308.38 g/mol, mp = 106–108 °C, 99+% purity, Lot: A0230775), was purchased from Acros Organics (Morris Plains, NJ) and used as received. Use tests for carbamazepine and phenylbutazone were carried out by differential scanning calorimetry (DSC). However, the use test for cimetidine was performed by Fourier transform infrared spectroscopy (FTIR) instead because DSC was unable to clearly distinguish the polymorphs of cimetidine (57).
Table Ib: Characterization methods for four polymorphs and three monohydrates of cimetidine.
Solvents. Out of the 23 common solvents useful for scale-up, only the following 19 environmentally benign solvents were employed: n-heptane, xylene, p-xylene, ethyl acetate, toluene, methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), chloroform, tetrahydrofuran (THF), N,N-dimethylaniline (DMA), acetone, 1,4-dioxane, n-butyl alcohol, isopropyl alcohol (IPA), acetonitrile, N,N-dimethylformamide (DMF), ethanol, methanol, and water (28–30). Two other solvents, n-propanol and cyclohexane, were used to verify the solubility sphere in the three-dimensional (3-D) Hansen plot.
Table Ic: Characterization methods for six polymorphs and six solvates of phenylbutazone.
Initial solvent screening. Under the initial solvent screening, the 19 solvents for scale-up previously listed were chosen (28–30, 70). About 5 mg of the API powders were weighed in a 20-mL scintillation vial the first time. Drops of a given solvent were titrated carefully by a micropipette into the vial with 1–2-min intermittent shaking until all the API powders were just dissolved at 25 °C, maintained by a water bath. The solubility of the API powders in that particular solvent was approximated as the weight of the API powders in the vial divided by the total volume of the solvent added to the vial (i.e., the gravimetric method). A good solvent was defined as a solvent that gave a solubility of ≥ 5 mg/mL at 25 °C and was designated by a yellow color. A bad solvent was designated by a red color later in the form space. The solubility of the API in the good solvent at 15, 40, and 60 °C (or 50 °C if the boiling point of a solvent is close to 60 °C) was measured by the gravimetric method assuming the volumes of solvents were the volumes of solution and the volumes of solvents did not change significantly with temperature. Although the gravimetric method appeared to be imprecise, its advantages were its robustness, simplicity, the low amount of API required, the lack of necessity for calibration, and the absence of solvate and hydrate formation.
Figure 3a: Polymorphic flow chart showing the preparation methods for the four anhydrous polymorphs of carbamazepine, the thermal transition of Forms IIâIV to Form I, and relationships (in blue) between carbamazepine Form I and Dihydrate I, and Form III and Dihydrate III.
Solvent-miscibility studies. Of the 19 solvents, about 1-mL portions of each solvent in a pair were intermittently shaken together for about 1–2 min in a 20-mL scintillation vial (28–30). The solvent pair was considered to be miscible if no interfacial meniscus was observed after the contents of the vial were allowed to settle. Otherwise, the pair was regarded as immiscible and designated by a gray color later in the form space.
Figure 3b: Polymorphic flow chart showing the preparation methods for the four anhydrous polymorphs of cimetidine; the mechanical, thermal, and solution transition among Forms AâD; the preparation methods of the three monohydrates; and thermal transition (in blue) of cimetidine Monohydrate I to Forms AâC.
Solids generation. Based on the predetermined solubility curves, solids generation of the API in each good solvent was achieved separately in a 20-mL scintillation vial by cooling the saturated API solution at 60 °C and by moving the vial from a 60 °C water bath to a 25 °C water bath with intermittent shaking (28–30). The crystal habits of all solids were characterized by optical microscopy (OM) inside the vial under a slurry state. All solids were filtered, oven-dried under mild conditions at 40 °C overnight, and characterized for their purity, polymorphism, solvates, and crystallinity by DSC, thermal gravimetric analysis (TGA), and transmission FTIR.
Figure 3c: Polymorphic flow chart showing preparation methods for the six anhydrous polymorphs of phenylbutazone; the thermal transition and the solution transformation among Forms Î±, Î², Î´, Îµ, and Î¶; the methods of preparation of six solvates; and thermal transition (in blue) to Form Î´.
OM. An optical microscope (SZII, Olympus, Tokyo) equipped with a charged-coupled device (CCD) camera (SSC-DC50A, Sony, Tokyo) was used to take images of crystal habit.
DSC. Thermal analytical data of 3–5 mg of solids placed in perforated, aluminum-sealed 60-µL pans were collected on a calorimeter (DSC-7, Perkin Elmer Instruments, Shelton, CT) with a temperature-scanning rate of 10 °C/min from 50 to 200 °C for carbamazepine 5 °C/min from 50 to 170 °C for cimetidine (mainly for the crystallinity measurements), and 8 °C/min from 50 to 130 °C for phenylbutazone using nitrogen 99.990% as a blanket gas (36, 43, 57, 62). The temperature axis was calibrated with indium 99.999 % (Perkin Elmer Instruments) with a melting onset at 156.6 °C. DSC provided the thermodynamic relationship between different polymorphs (i.e., forms) and information about crystallinity and the melting point of the API solids. The percent of crystallinity was calculated by dividing the area of a sample melting peak by the largest melting peak area of all samples.
TGA. TGA analysis was carried out by TGA heating balance (TGA 7, Perkin Elmer Instruments) to monitor sample weight loss as a function of temperature. The heating rate was 10 °C/min from 50 to 200 °C, 5 °C/min from 50 to 170 °C, and 8 °C/min from 50 to 130°C for carbamazepine, cimetidine, and phenylbutazone, respectively (36, 43, 57, 62). Weight loss was usually associated with either solvent evaporation close to the boiling point of a solvent, as in the case of solvates, or sample decomposition. The open platinum pan and stirrup were rinsed by ethanol and burned by a spirit lamp to remove all impurities. All samples were heated under nitrogen atmosphere to avoid oxidization. About 3 mg of sample were placed on the open platinum pan suspended in a heating furnace.
Transmission FTIR spectroscopy. Transmission FTIR spectroscopy was used to measure purity, detect bond formation, and verify chemical identity. Transmission FTIR spectra were recorded on a spectrometer (Spectrum One, Perkin Elmer Instruments). Approximately 1 mg of sample was ground gently with 99 mg of 50 °C oven-dried KBr in an agate mortar and pestle to avoid polymorphic transition induced by extended grinding. The round KBr sample disk was prepared by a uniaxial press with a pressure of 7 tons. The disk was scanned with a scan number of 8 from 450 to 4000 cm-1, with a resolution of 2 cm-1.
This work was supported by a grant from the National Science Council of Taiwan (NSC 95-2113-M-008-012-MY2). Suggestions from Jui-Mei Huang, of the Precision Instrument Center in National Central University, about DSC and from Ching-Tien Lin, also of the Precision Instrument Center in National Central University, about SEM are gratefully acknowledged.
Tu Lee* is an associate professor, and Yan Chan Su, Hung Ju Hou, and Hsiang Yu Hsieh are graduate students, all at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC, tel. +886 3 422 7151 ext. 34204, fax 886 3 425 2296, firstname.lastname@example.org
*To whom all correspondence should be addressed.
Submitted: July 8, 2008. Accepted: Sept. 15, 2008.
The results and related discussion will be included in Part 2 of this article, which will appear in the June issue of Pharmaceutical Technology.
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1. Y. Kawashima and C.E. Capes, "An Experimental Study of the Kinetics of Spherical Agglomeration in a Stirred Vessel," Powder Technol. 10 (1–2), 85–92 (1974).
2. Y. Kawashima and C.E. Capes, "Further Studies of the Kinetics of Spherical Agglomeration in a Stirred Vessel," Powder Technol. 13 (2), 279–288 (1976).
3. Y. Kawashima, M. Okumura, and H. Takenaka, "Spherical Crystallization: Direct Spherical Agglomeration of Salicylic Acid Crystals During Crystallization," Science 216 (4550), 1127–1128 (1982).
4. Y. Kawashima et al., "Preparation of Spherically Agglomerated Crystals of Aminophylline," J. Pharm. Sci. 73 (10), 1407–1409 (1984).
5. Y. Kawashima, M. Okumura, and H. Takenaka, "The Effects of Temperature on the Spherical Crystallization of Salicylic Acid," Powder Technol. 39 (1), 41–47 (1984).
6. Y. Kawashima et al., "Preparations of Agglomerated Crystals of Polymorphic Mixtures and a New Complex of Indomethacin-Epirizole by the Spherical Crystallization Technique," J. Pharm. Sci. 74 (11), 1152–1156 (1985).
7. A. Sano et al., "Particle Design of Tolbutamide by the Spherical Crystallization Technique II: Factors Causing Polymorphism of Tolbutamide Spherical Agglomerates," Chem. Pharm. Bull. 37 (8), 2183–2187 (1989).
8. Y. Kawashima et al., "Characterization of Polymorphs of Tranilast Anhydrate and Tranilast Monohydrate When Crystallized by Two Solvent Change Spherical Crystallization Techniques," J. Pharm. Sci. 80 (5), 472–478 (1991).
9. K. Morishima et al., "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).
10. Y. Kawashima et al., "Improvements in Flowability and Compressibility of Pharmaceutical Crystals for Direct Tabletting by Spherical Crystallization with a Two-Solvent System," Powder Technol. 78 (2), 151–157 (1994).
11. K. Morishima et al., "Tabletting Properties of Bucillamine Agglomerates Prepared by the Spherical Crystallization Technique," Int. J. Pharm. 105 (11), 11–18 (1994).
12. A.M. Garcia and E.S. Ghaly, "Preliminary Spherical Agglomerates of Water Soluble Drug Using Natural Polymer and Cross-Linking Technique," J. Control. Release 40 (3), 179–186 (1996).
13. A.H.L. Chow and M.W.M. Leung, "A Study of the Mechanisms of Wet Spherical Agglomeration of Pharmaceutical Powders," Drug Dev. Ind. Pharm. 22 (4), 357–371 (1996).
14. U. Teipel, T. Heintz, and H.H. Krause, "Crystallization of Spherical Ammonium Dinitramide (ADN) Particles," Propellants, Explosives, Pyrotechnics 25 (2), 81–85 (2000).
15. P. Szabó-Révész et al., "Development of Spherical Crystal Agglomerates of an Aspartic Acid Salt for Direct Tablet Making," Powder Technol. 114 (1), 118–124 (2001).
16. A.R. Paradkar et al., "Spherical Crystallization of Celecoxib," Drug Dev. Ind. Pharm. 28 (10), 1213–1220 (2002).
17. P. Szabó -Révész et al., "Crystal Growth of Drug Materials by Spherical Crystallization," J. Cryst. Growth 237–239 (part 3), 2240–2245 (2002).
18. Y. Kawashima et al., "Improved Flowability and Compactibility of Spherically Agglomerated Crystals of Ascorbic Acid for Direct Tableting Designed by Spherical Crystallization Process," Powder Technol. 130 (1), 283–289 (2003).
19. A.P. Pawar et al., "Crystallo-co-agglomeration: A Novel Technique to Obtain Ibuprofen-Paracetamol Agglomerates," AAPS Pharm. Sci. Tech., 5 (3), Article 44 (2004).
20. S. Bhadra et al., "Spherical Crystallization of Mefenamic Acid," Pharm. Technol. 28 (2), 66–76 (2004).
21. M. Maghsoodi et al., "Improved Compaction and Packing Properties of Naproxen Agglomerated Crystals Obtained by Spherical Crystallization Technique," Drug Dev. Ind. Pharm. 33 (11), 1216–1224 (2007).
22. J. Katta and å.C. Rasmuson, "Spherical Crystallization of Benzoic Acid," Int. J. Pharm. 348 (1–2), 61–69 (2008).
23. X. Liu et al., "Single-Crystal-like Materials by the Self-Assembly of Cube-Shaped Lead Zirconate Titanate (PZT) Microcrystals," Langmuir 21 (8), 3207–3212 (2005).
24. A.S. Utada et al., "Monodisperse Double Emulsions Generated from a Microcapillary Device," Science 308 (5721), 537–541 (2005).
25. S. Gupta and S.P. Moulik, "Biocompatible Microemulsions and Their Prospective Uses in Drug Delivery," J. Pharm. Sci. 97 (1), 22–45 (2008).
26. K. Ujiiye-Ishii et al., "Methodological Features of the Emulsion and Reprecipitation Methods for Organic Nanocrystal Fabrication," Cryst. Growth Des. 8 (2), 369–371 (2008).
27. T. Lee and S.T. Hung, "Cocktail-Solvent Screening to Enhance Solubility, Increase Crystal Yield, and Induce Polymorphs," Pharm. Technol. 32 (1), 76–95 (2008).
28. T. Lee, C.S. Kuo, and Y.H. Chen, "Solubility, Polymorphism, Crystallinity, and Crystal Habit of Acetaminophen and Ibuprofen," Pharm. Technol. 30 (10), 72–92 (2006).
29. T. Lee, Y.H. Chen, and C.W. Zhang, "Solubility, Polymorphism, Crystallinity, Crystal Habit, and Drying Scheme of (R,S)-(±)-Sodium Ibuprofen Dihydrate," Pharm. Technol. 31 (6), 72–87 (2007).
30. T. Lee and M.S. Lin, "Sublimation Point Depression of Tris(8-hydroxyquinoline)aluminum(III) (Alq3) by Crystal Engineering," Cryst. Growth Des. 7 (9), 1803–1810 (2007).
31. J. Alsenz and M. Kansy, "High Throughput Solubility Measurement in Drug Discovery and Development," Adv. Drug Deliv. Rev. 59 (7), 546–567 (2007).
32. T. Umeda et al., "Kinetics of the Thermal Transition of Carbamazepine Polymorphic Forms in the Solid State," Yakugaku Zasshi 104 (7), 786–792 (1984).
33. M.M.J. Lowes et al., "Physicochemical Properties and X-ray Structural Studies of the Trigonal Polymorph of Carbamazepine," J. Pharm. Sci. 76 (9), 744–752 (1987).
34. F.U. Krahn and J.B. Mielck, "Relations between Several Polymorphic Forms and the Dihydrate of Carbamazepine," Pharm. Acta Helv. 62 (9), 247–254 (1987).
35. J. Dugué et al., "Polymorphism of Carbamazepine: Solid-State Studies on Carbamazepine Dihydrate," Pharm. Acta Helv. 66 (11), 307–310 (1991).
36. L.E. McMahon et al, "Characterization of Dihydrates Prepared from Carbamazepine Polymorphs," J. Pharm. Sci. 85 (10), 1064–1069 (1996).
37. I. Katzhendler, R. Azoury, and M. Friedman, "Crystalline Properties of Carbamazepine in Sustained Release Hydrophilic Matrix Tablets Based on Hydroxypropyl Methylcellulose," J. Control. Release 54 (1), 69–85 (1998).
38. Y. Kobayashi et al., "Physicochemical Properties and Bioavailability of Carbamazepine Polymorphs and Dihydrate," Int. J. Pharm. 193 (2), 137–146 (2000).
39. C. Rustichelli et al., "Solid-State Study of Polymorphic Drugs: Carbamazepine," J. Pharm. Biomed. Anal. 23 (1), 41–54 (2000).
40. R. Nair, S. Gonen, and S.W. Hoag, "Influence of Polyethylene Glycol and Povidone on the Polymorphic Transformation and Solubility of Carbamazepine," Int. J. Pharm. 240 (1–2), 11–22 (2002).
41. Y. Yoshihashi, E. Yonemochi, and K. Terada, "Estimation of Initial Dissolution Rate of Drug Substance by Thermal Analysis: Application for Carbamazepine Hydrate," Pharm. Dev. Technol. 7 (1), 89–95 (2002).
42. A. Cvetkovskii et al., "Thermal Properties of Binary Mixtures of β-Cyclodextrin with Carbamazepine Polymorphs," J. Therm. Anal. Calorim. 68 (2), 669–678 (2002).
43. A. L. Grzesiak et al., "Comparison of the Four Anhydrous Polymorphs of Carbamazepine and the Crystal Structure of Form I," J. Pharm. Sci. 92 (11), 2260–2271 (2003).
44. R. Hilfiker et al., "Polymorphism—Integrated Approach from High-Throughput Screening to Crystallization Optimization," J. Therm. Anal. Calorim. 73 (2) 429–440 (2003).
45. S.G. Fleischman et al., "Crystal Engineering of the Composition of Pharmaceutical Phases: Multiple-Component Crystalline Solids Involving Carbamazepine," Cryst. Growth Des. 3 (6), 909–919 (2003).
46. N. Rodríguez-Hornedo and D. Murphy, "Surfactant-Facilitated Crystallization of Dihydrate Carbamazepine during Dissolution of Anhydrous Polymorph," J. Pharm. Sci. 93 (2), 449–460 (2004).
47. H.G. Brittain, "Fluorescence Studies of the Transformation of Carbamazepine Anhydrate Form III to Its Dihydrate Phase," J. Pharm. Sci. 93 (2), 375–383 (2004).
48. C. McGregor et al., "The Use of High-Speed Differential Scanning Calorimetry (Hyper-DSC) to Study the Thermal Properties of Carbamazepine Polymorphs," Thermochimica Acta 417 (2), 231–237 (2004).
49. A.J. Cruz Cabeza et al., "Importance of Molecular Shape for the Overall Stability of Hydrogen Bond Motifs in the Crystal Structures of Various Carbamazepine-Type Drug Molecules," Cryst. Growth Des. 7 (1), 100–107 (2007).
50. K. Seefeldt et al., "Crystallization Pathways and Kinetics of Carbamazepine–Nicotinamide Cocrystals from the Amorphous State by In Situ Thermomicroscopy, Spectroscopy, and Calorimetry Studies," J. Pharm. Sci. 96 (5) 1147–1158 (2007).
51. F. Tian et al., "Influence of Polymorphic Form, Morphology, and Excipient Interactions on the Disoolution of Carbamazepine Compacts," J. Pharm. Sci. 96 (3), 584–594 (2007).
52. M. Shibata et al., "X-Ray Structural Studies and Physicochemical Properties of Cimetidine Polymorphism," J. Pharm. Sci. 72 (12), 1436–1442 (1983).
53. B. Hegedüs and S. Görög, "The Polymorphism of Cimetidine," J. Pharm. Biomed. Anal. 3 (4), 303–313 (1985).
54. S. Sudo, K. Sato, and Y. Harano, "Solubilities and Crystallization Behavior of Cimetidine Polymorphic Forms A and B," J. Chem. Eng. Japan 24 (2), 237–242 (1991).
55. A. M. Tudor et al., "The Applications of Near-Infrared Fourier Transform Raman Spectroscopy to the Analysis of Polymorphic Forms of Cimetidine," Spectrochim. Acta 47A (9/10), 1389–1393 (1991).
56. E. Hädicke, F. Frickel, and A. Franke, "Die Struktur von Cimetidin (N"-Cyan-N-Methyl-N'-[2-[(5-methyl-1H-imidazol-4-yl)methylthio] ethyl]guanidine), einem Histamin H2-Rezeptor-Antagonist," Chem. Ber. 111 (9), 3222–3232 (1978).
57. A. Bauer-Brandl, "Polymorphic Transitions of Cimetidine during Manufacture of Solid Dosage Forms," Int. J. Pharm. 140 (2), 195–206 (1996).
58. A. Bauer-Brandl et al., "Comparison of Experimental Methods and Theoretical Calculations on Crystal Energies of 'Isoenergetic' Polymorphs of Cimetidine," J. Therm. Anal. Calorim. 57 (1), 7–22 (1999).
59. W.A. Bueno and E.G. Sobrinho, "Hydrogen Bonds in the Cimetidine Molecule," Spectrochim. Acta 51A (2), 287–292 (1995).
60. H.G. Ibrahim, F. Pisano, and A. Bruno, "Polymorphism of Phenylbutazone: Properties and Compressional Behavior of Crystals," J. Pharm.Sci. 66 (5) 669–673 (1977).
61. Y. Matsuda et al., "Polymorphism of Phenylbutazone by a Spray Drying Method," J. Pharm. Pharmacol. 32 (8), 579–580 (1980).
62. M.D. Tuladhar, J.E. Carless, and M.P. Summers, "Thermal Behavior and Dissolution Properties of Phenylbutazone Polymorphs," J. Pharm. Pharmacol. 35 (4), 208–214 (1983).
63. Y. Matsuda et al., "Physiochemical Characterization of Spray-Dried Phenylbutazone Polymorphs," J. Pharm. Sci. 73 (2), 173–179 (1984).
64. H.H. Paradies, "Structure of Phenylbutazone and Mofebutazone in the Crystalline State and in Solution," J. Pharm. Sci. 76 (12), 920–929 (1987).
65. T. Matsumoto et al., "Effect of Environmental Temperature on the Polymorphic Transformation of Phenylbutazone during Grinding," Chem. Pharm. Bull. 36 (3), 1074–1085 (1988).
66. N. Kaneniwa, J.I. Ichikawa, and T. Matsumoto, "Preparation of Phenylbutazone Polymorphs and Their Transformation in Solution," Chem. Pharm. Bull. 36 (3), 1063–1073 (1988).
67. Á. Beretzky et al., "Pelletization of Needle-Shaped Phenylbutazone crystals," J. Therm. Anal. Calorim. 69 (2), 529–539 (2002).
68. T. Hosokawa et al., "Isostructurality among Five Solvates of Phenylbutazone," Cryst. Growth Des. 4 (6), 1195–1201 (2004).
69. T. Hosokawa et al., "Relationships between Crystal Structures and Thermodynamic Properties of Phenylbutazone Solvates," Cryst. Eng. Comm. 6 (44), 243–249 (2004).
70. N.G. Anderson, "Solvent Selection," in Practical Process Research and Development (Academic Press, New York, 1st ed., 2000), pp. 81–111.