Amorphous besifloxacin solid
View Patent ↗Amorphous solid-state form of (R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is characterized by at least one of: (a) an X-ray powder diffraction (“XRPD”) spectrum that comprises peaks at 2θ angles of 6.9-7.1, 9.4, 10.6-10.7, and 13.4-13.7°±0.2°, and a diffuse halo pattern at 11-30°; and (b) a DSC (differential scanning calorimetry) melting peak at about 267-272° C. The amorphous solid is prepared by rapid precipitation from a saturated or supersaturated solution of besifloxacin free base in a solvent comprising at least benzyl alcohol.
1. An amorphous solid-state form of (R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1-cyclopropyl-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid characterized by an X-ray powder diffraction (“XRPD”) spectrum that comprises peaks at 2θ angles of 6.9-7.1, 9.4, 10.6-10.7, and 13.4-13.7°±0.2°, and a diffuse halo pattern at 11-30°.
2. An amorphous solid-state form of (R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1-cyclopropyl-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid characterized by a DSC (differential scanning calorimetry) melting peak at about 267-272° C.
3. The amorphous solid-state form of (R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1-cyclopropyl-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of claim 2 , wherein the amorphous solid-state form is further characterized by a DSC (differential scanning calorimetry) melting peak at about 267-272° C.
4. A process for preparing an amorphous besifloxacin solid comprising: (a) preparing a first saturated solution of besifloxacin free base in benzyl alcohol at a first temperature in the range from about 60 to about 180° C.; (b) reducing the temperature of the solution to a second temperature in the range from about −10 to about 40° C.; (c) preparing a second saturated solution of besifloxacin free base in a second organic solvent other than benzyl alcohol at said second temperature, said second organic solvent being soluble in benzyl alcohol at said second temperature; (d) adding an amount of said second saturated solution to said first saturated solution at said second temperature to form a mixture; and (e) holding said mixture at said second temperature for a time from about 10 minutes to about 4 weeks, whereby said amorphous besifloxacin solid is formed.
5. The process of claim 4 , wherein said amorphous besifloxacin free base is characterized by an X-ray powder diffraction (“XRPD”) spectrum that comprises peaks at 2θ angles of 6.9-7.1, 9.4, 10.6-10.7, and 13.4-13.7°±0.2°, and a diffuse halo pattern at 11-30°.
6. The process of claim 4 , further comprising: (f) recovering said amorphous besifloxacin solid from said solution; and (g) removing benzyl alcohol and said second organic solvent from said amorphous besifloxacin solid.
7. The process of claim 4 , wherein said amorphous besifloxacin free base is characterized by an X-ray powder diffraction (“XRPD”) spectrum that comprises peaks at 2θ angles of 6.9-7.1, 9.4, 10.6-10.7, and 13.4-13.7°±0.2°, and a diffuse halo pattern at 11-30°, and a DSC (differential scanning calorimetry) melting peak at about 267-272° C.
8. The process of claim 6 , wherein said removing is carried out at subatmospheric pressure at a temperature from about room temperature to about 50° C.
9. A process for preparing an amorphous besifloxacin solid comprising: (a) preparing a first saturated solution of besifloxacin free base in benzyl alcohol at a first temperature in the range from about 80 to about 140° C.; (b) reducing the temperature of the solution to a second temperature in the range from about −10 to about 25° C.; (c) holding the solution at said second temperature for 10 minutes to 4 weeks, whereby said amorphous besifloxacin solid is formed.
10. The process of claim 9 , wherein said amorphous besifloxacin free base is characterized by an X-ray powder diffraction (“XRPD”) spectrum that comprises peaks at 2θ angles of 6.9-7.1, 9.4, 10.6-10.7, and 13.4-13.7°±0.2°, and a diffuse halo pattern at 11-30°.
11. The process of claim 10 , further comprising repeating step (e) at least more time.
12. The process of claim 10 , wherein said amorphous besifloxacin free base is characterized by an X-ray powder diffraction (“XRPD”) spectrum that comprises peaks at 2θ angles of 6.9-7.1, 9.4, 10.6-10.7, and 13.4-13.7°±0.2°, and a diffuse halo pattern at 11-30°, and a DSC (differential scanning calorimetry) melting peak at about 267-272° C.
13. A process for preparing an amorphous besifloxacin solid comprising: (a) preparing a first saturated solution of besifloxacin free base in benzyl alcohol at a first temperature in the range from about 60 to about 180° C.; (b) reducing the temperature of the solution to a second temperature in the range from about −10 to about 40° C.; (c) preparing a second saturated solution of besifloxacin free base in a second organic solvent other than benzyl alcohol at said second temperature, said second organic solvent being soluble in benzyl alcohol at said second temperature; (d) adding an amount of said second saturated solution to said first saturated solution at said second temperature to form a mixture; (e) holding said mixture at said second temperature for a time from about 10 minutes to about 4 weeks, whereby said amorphous besifloxacin solid is formed; (f) repeating step (e) at least more time; (g) recovering said amorphous besifloxacin solid from said solution; and (h) removing benzyl alcohol and said second organic solvent from said amorphous besifloxacin solid.
14. The process of claim 13 , wherein said amorphous besifloxacin free base is characterized by an X-ray powder diffraction (“XRPD”) spectrum that comprises peaks at 2θ angles of 6.9-7.1, 9.4, 10.6-10.7, and 13.4-13.7°±0.2°, and a diffuse halo pattern at 11-30°, and a DSC (differential scanning calorimetry) melting peak at about 267-272° C.