Novel crystalline forms of gatifloxacin and processes for preparation
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsEhud Amir, Valerie Niddam-Hildesheim, Greta Sterinbaum, Shlomit Wizel
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Abstract
Provided are novel crystalline forms of gatifloxacin, some of which are DMSO solvates, and methods for making them.
Claims84
A crystalline DMSO solvate of gatifloxacin characterized by at least one characteristic selected from:
- a) x-ray reflections at about 14.7, 16.3, 17.6, and 19.7°±0.2° 2θ, and
- b) endothermic peaks at about 133° and about 167° C. in DSC.
A crystalline DMSO solvate of gatifloxacin characterized by:
- a) x-ray reflections at about 14.7, 16.3, 17.6, and 19.7°±0.2°2θ, and
- b) endothermic peaks at about 133° and about 167°0 C. in DSC.
A crystalline DMSO solvate of gatifloxacin characterized by at least one characteristic selected from:
- a) x-ray reflections at about 6.5, 14.6, 17.4, and 19.4°±0.2°2θ, and
- b) endothermic peaks at about 122° and about 137° in DSC.
The crystalline DMSO solvate of gatifloxacin characterized by x-ray reflections at about 6.5, 14.6, 17.4, and 19.4°±0.2 °2θ.
A crystalline DMSO solvate of gatifloxacin characterized by:
- a) x-ray reflections at about 6.5, 14.6, 17.4, and 19.4°±0.2°2θ, and
- b) endothermic peaks at about 122° and about 137° in DSC.
A crystalline form of gatifloxacin characterized by at least one of:
- a) x-ray reflections at about 5.2, 11.2, 11.5, 14.3, and 22.2°±0.2°2θ, and
- b) an endothermic peak at about 178° C. in DSC.
A crystalline form of gatifloxacin characterized by:
- a) x-ray reflections at about 5.2, 11.2, 11.5, 14.3, and 22.2°±0.2°2θ, and
- b) an endothermic peak at about 178° C. in DSC.
A crystalline form of gatifloxacin characterized by at least one of:
- a) x-ray reflections at about 6.6, 7.2, 13.2, 17.6, 19.8, and 23.0°±0.2° θ. and
- b) an endotherm at about 122° C. in DSC.
The crystalline form of gatifloxacin of claim 28 characterized by an endotherm at about 122° C. in DSC.
A crystalline form of gatifloxacin characterized by:
- a) x-ray reflections at about 6.6, 7.2, 13.2, 17.6, 19.8, and 23.0°±0.2° θ, and
- b) an endotherm at about 122° C. in DSC.
A crystalline form of gatifloxacin characterized by at least one of:
- a) x-ray reflections at about 7.8, 10.8, 13.7, 18.6, and 19.9°±0.2° 2θ, and
- b) endotherms at about 90° and about 175° C. in DSC.
A crystalline form of gatifloxacin characterized by:
- a) x-ray reflections at about 7.8, 10.8, 13.7, 18.6, and 19.9°±0.2° 2θ, and
- b) endotherms at about 90° and about 175° C. in DSC.
A crystalline form of gatifloxacin characterized by at least one of:
- a) x-ray reflections at about 13.4, 14.8, 17.6, 19.6, and 20.0°±0.2° 2θ, and
- b) an endotherm at about 99° C. in DSC.
A crystalline form of gatifloxacin characterized by at least one of:
- a) x-ray reflections at about 13.9, 14.8, and 16.1°±0.2°2θ, and
- b) endotherms at about 92° and about 188° C. in DSC.
A crystalline form of gatifloxacin characterized by:
- a) x-ray reflections at about 13.9, 14.8, and 16.1°±0.2°2θ, and
- b) endotherms at about 92° and about 188° C. in DSC.
A crystalline form of gatifloxacin characterized by at least one of:
- a) x-ray reflections at about 6.7, 9.5, 10.7, 13.1, 17.2°±0.2° 2θ, and
- b) endotherms at about 65°, 90°, and 190° C. in DSC, wherein the endotherm at 190° C. is sharper than the other endotherms.
A crystalline form of gatifloxacin characterized by:
- a) x-ray reflections at about 6.7, 9.5, 10.7, 13.1, 17.2°±0.2° 2θ, and
- b) endotherms at about 65°, 90°, and 190° C. in DSC, wherein the endotherm at 190° C. is sharper than the other endotherms.
A crystalline form of gatifloxacin characterized by x-ray reflections at about 5.5, 10.3, 10.8, 13.9, and 15.1°±0.2° 2θ.
A crystalline form of gatifloxacin characterized by x-ray reflections at about 7.8, 9.1, 9.4, and 9.6°±0/2° 2θ.
A crystalline form of gatifloxacin characterized by x-ray reflections at about 6.6, 9.9, 10,5, and 12.9°±0.2° 2θ.
A crystalline form of gatifloxacin characterized by x-ray reflections at about 6.3, 9.3, 19.3, 20.8, 24.5, and 25.1°±0.2° 2θ.
A crystalline forrn of gatifloxacin characterized by x-ray reflections at 6.4, 9.4, 16.4, 18.9, and 19.2°±0.2° 2.
A method of making a crystalline form of gatifloxacin having at least one characteristic of form CX comprising the steps of:
- a) combining an initial solution of gatifloxacin in DMSO with water at a temperature of about 55° C.,
- b) cooling the combination to a temperature of about 0° C. at a coling rate of about 10° per hour whereby a suspension is obtained,
- c) isolating the crystalline form of gatifloxacin having at least one characteristic of form CX from the suspension, and
- d) washing the isolated crystalline form of gatifloxacin with sufficient acetonitrile to maintain the crystalline form as form CX.
A method of making a crystalline form of gatifloxacin having at least one characteristic of form CW comprising the steps of:
- a) providing gatifloxacin form CX, and
- d) drying the gatifloxacin form CX at reduced pressure for about 8 hours to obtain the crystalline form having at least one characteristic of form CW.
A method of making a crystalline form of gatifloxacin having at least one characteristic of form CY comprising the steps of:
- a) providing an initial solution of gatifloxacin in DMSO at a concentration of at least about 2 M and a temperature of about 40° C.,
- b) combining the solution with water at a temperature of about 40° C.,
- c) cooling the solution to a temperature of about 5° C. and maintaining the suspension obtained at about 5° C. for a holding time,
- d) isolating DMSO-wet solid gatifloxacin from the suspension,
- e) suspending the isolated DMSO-wet solid gatifloxacin in acetonitrile,
- f) isolating the gatifloxacin from the suspension, and
- g) drying the isolated gatifloxacin at about 50° C. and <<reduced pressure>> for at least about 12 hours.
A method of making a crystalline form of gatifloxacin having at least one characteristic of form CZ comprising the steps of:
- a) providing an initial solution of gatifloxacin in DMSO at about 55° C.,
- b) combining, at about 55° C., the provided solution with water and toluene, 1:2 to 1:3, vol:vol,
- c) cooling the resulting mixture to about 11° C. at a cooling rate of about 10° per hour,
- d) heating the mixture to about 35° C. and maintaining the mixture at this temperature for about 1 hour,
- e) cooling the mixture to about 11° C. at a cooling rate of about 4° per hour,
- f) maintaining the resulting suspension at about 10° C. for a holding time,
- g) isolating the gatifloxacin having at least one characteristic of form CZ from the suspension obtained, and
- h) washing the isolated gatifloxacin with acetonitrile.
A method of making a crystalline form of gatifloxacin having at least one characteristic of form W comprising the steps of:
- a) providing, at reflux temperature, a solution of gatifloxacin in acetonitrile,
- b) combining, at reflux temperature, the solution with about one-tenth of its volume of polyethylene glycol,
- c) cooling the resulting solution to about 57° C. and seeding the solution with gatifloxacin hemihydrate,
- d) maintaining the seeded solution at about 57° C. for about 2 hours,
- e) cooling the resulting seeded solution to about 5° C. at about 5° per hour,
- f) maintaining the resulting suspension at about 5° C. for a holding time,
- g) isolating crystalline gatifloxacin the suspension,
- h) washing the isolated crystalline gatifloxacin with acetonitrile, and
- i) drying the isolated, acetonitrile-washed crystalline gatifloxacin to obtain gatifloxacin having at least one characteristic of form W.
A method of making a crystalline form of gatifloxacin having at least one characteristic of form Y comprising the steps of:
- a) providing a slurry of gatifloxacin hydrochloride in a 9:1, vol:vol, mixture of acetonitrile and water at a temperature of about 5° C.,
- b) combining the suspension with a volume of an aqueous solution of NaOH sufficient to neutralize at least about 70 mole % of the hydrochloride,
- c) isolating solid gatifloxacin from the resulting suspension,
- d) washing the isolated solid gatifloxacin with a 9:1, v:v mixture of acetonitrile and water, and
- e) drying the isolated solid gatifloxacin at about 50° C. and reduced pressure to obtain the crystalline form of gatifloxacin having at least one characteristic of form Y.
A method of making a crystalline form of gatifloxacin having at least one characteristic of form Z comprising the steps of:
- a) providing a hot-filtered solution of gatifloxacin in acetonitrile at about 80° C.,
- b) cooling the solution to about 60° C.,
- c) maintaining the filtered solution at about 60° C. for about 1 hour,
- d) cooling the solution to about 5° C. at a cooling rate of about 20° to about 25° per hour,
- e) maintaining the resulting suspension at about 5° C. for about 30 minutes,
- f) isolating the crystalline form of gatifloxacin having at least one characteristic of form Z from the suspension.
A method of making gatifloxacin in crystalline form CH1 comprising the step of heating gatifloxacin having at least one characteristic of form CY at about 100° C. for at least about 30 minutes.
A method of making gatifloxacin crystalline form RH comprising the step of heating gatifloxacin form R at about 50° C. to about 70° C.
A method of making gatifloxacin crystalline form V comprising the step of heating gatifloxacin crystalline form CZ at about 110° C. to about 130° C.
A method of making gatifloxacin in crystalline form T2RP comprising the step of heating gatifloxacin crystalline form CW at about 135° C. to about 150° C.
A method of making gatifloxacin in crystalline form HX1 comprising the steps of:
- a) suspending, at ambient temperature, DMSO-wet gatifloxacin,
- b) maintaining the suspension at ambient temperature for about 1 hour, and
- c) isolating gatifloxacin crystalline form HX1 from the suspension.
A method of making gatifloxacin in crystalline form HX2 comprising the steps of slurrying, at ambient temperature, gatifloxacin in water, at about 20% weight-to-volume, and isolating gatifloxacin in crystalline form HX2 from the suspension.
A pharmaceutical formulation comprising at least one pharmaceutically acceptable excipient and at least one crystalline form of gatifloxacin having at least one characteristic of a crystalline form of gatifloxacin selected from forms CW, CX, CY, CZ, W, X, Y, Z, CH1, CH2, RH, HX1, and HX2.
Dependencies are inferred from the claim text.