Description:
BACKGROUND OF INVENTION
1. Crystalline/polymorphic forms of drug under subject - Prulifloxacin (A Fluoroquinolone antibiotic), different from invented by us, have already been patented by other authors for International, US or European patent. Unlike to the crystalline forms reported in other patents: International Publication Number- WO 2008/111016 A1 and its corrected version WO 2008/111016 A9, International Publication Number- WO 2008/ 059512 A1, WO 2012/001357 A1, CN1704419A, U.S. Patent No. 5,086,049, EP 1,626,051 and 96/MUM/2009 we have prepared five (05) new crystalline forms of Prulifloxacin different from reported in above patents as evident from different analytical techniques – FTIR spectra, PXRD spectra, DSC and TGA performed on prepared crystal forms.
All above process patents describe Type I, Type II and Type III crystal forms of prulifloxacin prepared by different methods whereas only WO 2012/001357 A1 claims another crystal form- Form A and process for its preparation/synthesis. No other supportive technique than just PXRD has been given as evidence of invention of different processes in these patent applications, wherein reported crystalline forms are also different from the crystalline forms prepared by us as evident from above mentioned techniques.
2. Description of the related Art/Work:
The following specification describes the invention-
We have prepared following new crystalline forms of prulifloxacin-
Form B coded as ACN (SE)
Form C coded as DCM (SC)
Form D coded as DCM (SE)
Form E coded as DMF (SC)
Form F coded as DMF (SE)
Where ACN is code for solvent “Acetonitrile”,
DCM is code for solvent “Dichloromethane”,
DMF is code for solvent “Dimethyl formamide”;
SC is code for “Solvent Change” method of recrystallization,
SE is code for “Solvent Evaporation” method of recrystallization.
For preparation of these five new crystalline forms of prulifloxacin, we have used two processes- solvent evaporation and solvent change, different from the previously reported by others in pervious patents. Though we have used two well known processes of recrystallization- “Solvent Evaporation” and “Solvent Change” methods but the solvent used, parameters/conditions applied by us make these processes different from processes used in previous patents.
3. Under Solvent Evaporation method a suitable amount of drug was dissolved in solvent of choice at 40 degree Celsius. The hot solution was filtered through Whatman filter paper number 42 to remove any undissolved drug and kept in a beaker at 40 degree Celsius in an oven to evaporate the solvent. Recrystallized drug was scrapped off, washed with petroleum ether, dried in rota-vapour and stored in a dessicator. The solvents used were Acetonitrile, Dichloromethane and Dimethyl formamide.
4. Under Solvent Change method a suitable amount of drug was dissolved in 100 ml solvent at 60 degree Celsius to prepare supersaturated solution of the drug in the solvent. The hot solution was filtered through Whatman filter paper number 42 at the same temperature to remove any undissolved drug and added at once with stirring to 100 ml filtered distilled water kept at 4 degree Celsius in an ice bath on the magnetic stirrer. The precipitated material was collected by filtration and dried in an oven at 40 degree Celsius and then washed with petroleum ether, dried in rota-vapour and stored in a dessicator. The solvents used were Dichloromethane and Dimethylformamide.
5. New crystalline forms of prulifloxacin prepared by described methods were characterized by comparing the PXRD patterns with that of procured crystalline form of prulifloxacin. PXRD patterns have been shown in Figures 1 to 6.
The Powder X Ray Diffraction patterns of crystalline forms of prulifloxacin were measured on Bruker D8 X-Ray diffrectometer at 250C with points at 0.1 and diffraction angle 2? from 5 degree to 49.993 degree.

Figure 1: PXRD spectrum of new crystalline form B of Prulifloxacin

Figure 2: PXRD spectrum of new crystalline form C of Prulifloxacin

Figure 3 : PXRD spectrum of new crystalline form D of Prulifloxacin

Figure 4 : PXRD spectrum of new crystalline form E of Prulifloxacin

Figure 5: PXRD spectrum of new crystalline form F of Prulifloxacin

Figure 6: PXRD spectrum of Procured crystalline form of Prulifloxacin

6. New crystalline forms (B, C, D, E, F) of prulifloxacin have also been characterized by FTIR spectra as shown in Figures 7 to 11 and compared with FTIR spectra (Figure 12) of procured crystalline form of prulifloxacn.
FTIR spectra of prepared five crystalline forms of prulifloxacin were recorded using KBr pellets by SHIMADZU 8700, FTIR SPECTROMETER, (Japan) in the range of 250-4500cm-1.

Figure 7: FTIR spectrum of new crystalline form B of Prulifloxacin

Figure 8: FTIR spectrum of new crystalline form C of Prulifloxacin

Figure 9: FTIR spectrum of new crystalline form D of Prulifloxacin

Figure 10: FTIR spectrum of new crystalline form E of Prulifloxacin

Figure 11: FTIR spectrum of new crystalline form F of Prulifloxacin

Figure 12: FTIR spectrum of procured crystalline form of Prulifloxacin

Comparison of peaks in FTIR spectra of new crystalline forms with that of procured crystalline form:

New peaks 25 in ACN(SE)
09 in DCM(SC)
14 in DCM(SE)
12 in DMF(SC)
10 in DMF(SE)

Disappeared peaks : 19 in ACN(SE)
13 in DCM(SC)
21 in DCM(SE)
20 in DMF(SC)
17 in DMF(SE)

7. New crystalline forms (B, C, D, E) of prulifloxacin and procured form have also been characterized by DSC curves as shown in figures 13 to 17.
DSC endotherm spectra of prepared crystal forms B, C, D, E have been recorded using Perkin Elmer DSC-TGA apparatus in the range of 0 to 450 degree Celsius.

Figure 13: DSC Thermogram of new crystalline form B of Prulifloxacin

Figure 14: DSC Thermogram of new crystalline form C of Prulifloxacin

Figure 15: DSC Thermogram of new crystalline form D of Prulifloxacin

Figure 16: DSC Thermogram of new crystalline form E of Prulifloxacin

Figure 17: DSC Thermogram of procured crystalline form of prulifloxacin

8. New crystalline forms of prulifloxacin and procured crystalline form have also been characterized by TGA curves as shown in Figures 18 to 22.
TGA spectra of prepared crystal forms B, C, D, E have been recorded using Perkin Elmer DSC-TGA apparatus in the range of 0 to 500 degree Celsius.

Figure 18: TGA curve for new crystalline form B of Prulifloxacin

Figure 19: TGA curve for new crystalline form C of Prulifloxacin

Figure 20: TGA curve for new crystalline form D of Prulifloxacin

Figure 21: TGA curve for new crystalline form E of Prulifloxacin

Figure 22: TGA curve for procured crystalline form of Prulifloxacin

Claims:

We claim to invent following five new crystalline forms of fluoroquinolones antibiotic prulifloxacin:
1. New crystalline form B, coded as ACN (SE) which has been prepared by solvent evaporation method of recrystallization using solvent- Acetonitrile. A suitable amount of drug was dissolved in solvent Acetonitrile at 40 degree Celsius. The hot solution was filtered through Whatman filter paper no.42 to remove any undissolved drug and kept in 500 ml beaker for evaporation at 40 degree Celsius in an oven. Recrystallized form of prulifloxacin was scrapped off, washed with petroleum ether, dried in rota-vapour and stored in a desiccator for further characterization. The prepared crystalline form was characterized through PXRD, FTIR, DSC and TGA and compared with procured form of prulifloxacin. Remarkable differences in the spectra of new crystalline form B from that of spectra of procured prulifloxacin and spectra presented in other patents, if any, obtained by all the four techniques signify the crystalline form B to be entirely different form from those of previously reported crystalline forms of prulifloxacin and thus new crystalline form B of prulifloxacin is claimed to be invented.
2. New crystalline form C, coded as DCM (SC) which has been prepared by solvent change method of recrystallization using solvent- Dichloromethane. A suitable amount of drug was dissolved in 100 ml of Dichloromethane at 60 degree Celsius to prepare supersaturated solution of the drug in the solvent. The hot solution was filtered through Whatman filter paper number 42 at the same temperature to remove any undissolved drug. This supersaturated solution was added at once with stirring into 100 ml filtered distilled water kept at 4 degree Celsius in an ice bath on the magnetic stirrer. The precipitated material was collected by filtration and dried in an oven at 40 degree Celsius and then washed with petroleum ether, dried in rota-vapour and stored in desiccator for further characterization. The prepared crystalline form C was characterized through PXRD, FTIR, DSC and TGA and compared with procured form of prulifloxacin. Remarkable differences in the spectra of new crystalline form B from that of spectra of procured prulifloxacin and spectra presented in other patents, if any, obtained by all the four techniques signify the crystalline form C to be entirely different form from those of previously reported crystalline forms of prulifloxacin and thus new crystalline form C of prulifloxacin is claimed to be invented.
3. New crystalline form D, coded as DCM (SE) which has been prepared by solvent evaporation method of recrystallization using solvent- Dichloromethane. A suitable amount of drug was dissolved in solvent Dichloromethane at 40 degree Celsius. The hot solution was filtered through Whatman filter paper no. 42 to remove any undissolved drug and kept in 500 ml beaker for evaporation at 40 degree Celsius in an oven. Recrystallized form of prulifloxacin was scrapped off, washed with petroleum ether, dried in rota-vapour and stored in a desiccator for further characterization. The prepared crystalline form was characterized through PXRD, FTIR, DSC and TGA and compared with procured form of prulifloxacin. Remarkable differences in the spectra of new crystalline form D from that of spectra of procured prulifloxacin and spectra presented in other patents, if any, obtained by all the four techniques signify the crystalline form D to be entirely different form from those of previously reported crystalline forms of prulifloxacin and thus new crystalline form D of prulifloxacin is claimed to be invented.
4. New crystalline form E, coded as DMF (SC) which has been prepared by solvent change method of recrystallization using solvent- Dimethylformamide. A suitable amount of drug was dissolved in 100 ml of Dimethylformamide at 60 degree Celsius to prepare supersaturated solution of the drug in the solvent. The hot solution was filtered through Whatman filter paper number 42 at the same temperature to remove any undissolved drug. This supersaturated solution was added at once with stirring into 100 ml filtered distilled water kept at 4 degree Celsius in an ice bath on the magnetic stirrer. The precipitated material was collected by filtration and dried in an oven at 40 degree Celsius and then washed with petroleum ether, dried in rota-vapour and stored in desiccator for further characterization. The prepared crystalline form E was characterized through PXRD, FTIR, DSC and TGA and compared with procured form of prulifloxacin. Remarkable differences in the spectra of new crystalline form B from that of spectra of procured prulifloxacin and spectra presented in other patents, if any, obtained by all the four techniques signify the crystalline form E to be entirely different form from those of previously reported crystalline forms of prulifloxacin and thus new crystalline form E of prulifloxacin is claimed to be invented.
5. New crystalline form F, coded as DMF (SE) which has been prepared by solvent evaporation method of recrystallization using solvent- Dimethylformamide. A suitable amount of drug was dissolved in solvent Dimethylformamide at 40 degree Celsius. The hot solution was filtered through Whatman filter paper no.42 to remove any undissolved drug and kept in 500 ml beaker for evaporation at 40 degree Celsius in an oven. Recrystallized form of prulifloxacin was scrapped off, washed with petroleum ether, dried in rota-vapour and stored in a desiccator for further characterization. The prepared crystalline form was characterized through PXRD and FTIR and compared with procured form of prulifloxacin. Remarkable differences in the spectra of new crystalline form B from that of spectra of procured prulifloxacin and spectra presented in other patents, if any, obtained by all the four techniques signify the crystalline form F to be entirely different form from those of previously reported crystalline forms of prulifloxacin and thus new crystalline form F of prulifloxacin is claimed to be invented.