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CRYSTALLINE 2R, 3S-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-1-(1H-1,2,4-TRIAZOL-1-YL)-2-BUTANOL (VRC) IN PLATE-LIKE FORM AND MICRONIZED 2R, 3S-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-1-(1H-1,2,4-TRIAZOL-1-YL)-2-BUTANOL OBTAINED THEREFROM

IP.com Disclosure Number: IPCOM000125373D
Publication Date: 2005-May-31
Document File: 12 page(s) / 1M

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The IP.com Prior Art Database

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CRYSTALLINE 2R, 3S-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)- 1-(1H-1,2,4-TRIAZOL-1-YL)-2-BUTANOL (VRC) IN PLATE-LIKE FORM AND MICRONIZED 2R, 3S-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-1-

(1H-1,2,4-TRIAZOL-1-YL)-2-BUTANOL OBTAINED THEREFROM

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BACKGROUND

        VRC is an antifungal drug with a broad spectrum of bioactivity. VRC can be prepared as described, for example, in the following patents: EP 440372 B1, examples 7 and 8, and U.S. Patent No. 6,586,594, preparations 2, 4 and 8, and their equivalents, in which the final compound is isolated as a crystalline solid and not further purified. The only analytical data reported is 10 melting point (127°C, EP '372; 133°C, US '594) and specific optical rotation (-62°, EP '372).

        The scientific literature does not report the ability of VRC to crystallize into different crystal habits. Although a reactive crystallization process is disclosed in U.S. Patent No. 6,558,435 (Example 4: Crystallization of VRC Camphorsulfonic Acid Salt to VRC Free Base), crystal habit is not disclosed. 15

        It is reported that a product that crystallizes in the form of needles is difficult to filter, wash, and isolate. Such a product is said to have a very long drying time and to form very hard lumps during the drying process. Moreover, grinding of such a material can produce a dry powder that exhibits a strong tendency to accumulate electrostatic charge and is not very pourable. U.S. Patent No. 6,358,986 at col. 2, lines 28-41. See also Wadke, D. A. & Jacobson, 20

H. "Preformulation Testing." in H. A. Lieberman & L. Lachman (Eds.), Pharmaceutical Dosage Forms: Tablets (1980), vol. 1, and Newman, A. W. & Brittain, H. G. "Particle Morphology: Optical and Electron Microscopes." in H. G. Brittain (Ed.), Physical Characterization of Pharmaceutical Solids (1995).

Crystalline compounds, including crystalline active pharmaceutical ingredients (APIs)

25 may crystallize with different crystal habits (gross morphology of the crystalline particles). A needle-like crystal habit is undesirable in an API because handling of bulk material comprised of such particles can be problematic. For example, filtration of suspensions of such needle-like crystals is said to be difficult, and the bulk material comprised of such needle-like crystals can be subject to blocking or bridging in weighing, handling, and conveying equipment. Other 30 disadvantages are known. See U.S. Patent No. 6,358,986 at col. 2, lines 28-41. See also Wadke,


D. A. & Jacobson, H. "Preformulation Testing." in H. A. Lieberman & L. Lachman (Eds.), Pharmaceutical Dosage Forms: Tablets (1980), vol. 1, and Newman, A. W. & Brittain, H. G. "Particle Morphology: Optical and Electron Microscopes." in H. G. Brittain (Ed.), Physical

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Characterization of Pharmaceutical Solids (1995). Alternative crystal habits, for example a plate-like crystal habit, are preferred.

       Frequently, solid pharmaceutical products contain micronized active pharmaceutical ingr...