DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL CRYSTALLINE FORM OF GEPOTIDACIN MESYLATE AND PROCESS FOR PREPARATION

APITORIA PHARMA PRIVATE LIMITED HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to novel crystalline form of Gepotidacin Mesylate and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Gepotidacin Mesylate, chemically known as (2R)-2-[(4-{[(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl]-amino}piperidin-1-yl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione monomethine sulfonate dihydrate (compound of Formula 1), is the first in a new class of antibiotics, currently marketed as BLUJEPA® for the treatment of female adult and pediatric patients 12 years of age and older weighing at least 40 kilograms (kg) with uncomplicated urinary tract infections (uUTI) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus, and Enterococcus faecalis.

Formula 1

US Patent No. 8,389,524 discloses a series of compounds including Gepotidacin. A process for mono-hydrochloride salt of Gepotidacin is disclosed in the ‘524 patent.

US Patent Application No. 2023/0167113 discloses crystalline forms of Gepotidacin Mesylate such as Gepotidacin Mesylate Dihydrate Form 1, Gepotidacin Mesylate anhydrate Form 2 and Gepotidacin Mesylate monohydrate Form 3.

Considering the importance of Gepotidacin Mesylate, nevertheless, besides the known solid forms of Gepotidacin Mesylate, there is still the need for further polymorphs which are reproducible, are stable under stress conditions and formulation preparations.

In view of the above, the present invention related to crystalline form of Gepotidacin Mesylate which is stable, reproducible and commercially suitable process for the preparation thereof.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a crystalline form of Gepotidacin Mesylate and a process for the preparation thereof.

SUMMARY OF THE INVENTION

The present invention is directed to solid state form of Gepotidacin Mesylate, designated as crystalline Gepotidacin Mesylate Form GEP-1, characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 9.5; 10.9; 17.3; 18.1 and 19.6 ± 0.2° 2?.

The present invention further directed to process for the preparation of the crystalline Gepotidacin Mesylate GEP-1, which comprises;
a) dissolving Gepotidacin Mesylate or its hydrate in 2-butanol or mixture of 2-butanol and methanol to obtain a solution;
b) adding the solution of step a) to toluene;
c) stirring the above solution; and
d) obtaining the crystalline Gepotidacin Mesylate GEP-1.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: PXRD pattern of Gepotidacin Mesylate GEP-1.
Figure 2: DSC pattern of Gepotidacin Mesylate GEP-1.
Figure 3: TGA Thermogram of Gepotidacin Mesylate GEP-1.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides solid state Gepotidacin Mesylate, designated as Gepotidacin Mesylate GEP-1.

In other embodiment, the present invention provides crystalline Gepotidacin Mesylate, designated as GEP-1, having water content 0.5 to 2.5 % w/w.

In another embodiment, the present application provides crystalline Gepotidacin Mesylate Form GEP-1 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 9.5; 10.9; 17.3; 18.1 and 19.6 ± 0.2° 2?.

In another embodiment, the present application crystalline Gepotidacin Mesylate Form GEP-1 characterized by its PXRD pattern having additional peaks at 14.9; 20.6; 21.7; 23.5 and 30.1 ± 0.2° 2?.

In another embodiment, the present application provides crystalline Gepotidacin Mesylate Form GEP-1 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at 3.7; 7.4; 9.5; 10.9; 12.7; 13.2; 14.0; 14.9; 15.6; 16.1; 16.7; 17.3; 18.1; 18.7; 19.1; 19.6; 20.1; 20.6; 21.0; 21.7; 22.4; 23.5; 24.3; 24.9; 25.4; 26.6; 26.9; 27.3; 28.8 and 30.1 ± 0.2° 2?.

In another embodiment, the present invention provides a process for the preparation of the crystalline Gepotidacin Mesylate GEP-1
which comprises;
e) dissolving Gepotidacin Mesylate or its hydrate in 2-butanol or mixture of 2-butanol and methanol to obtain a solution;
f) adding the solution of step a) to toluene;
g) stirring the above solution; and
h) obtaining the crystalline Gepotidacin Mesylate GEP-1.

In another embodiment, the present invention provides a crystalline Gepotidacin Mesylate GEP-1 having a Powder X-ray Diffraction (PXRD) pattern shown in Figure-1.

In another embodiment, the present invention provides a crystalline Gepotidacin Mesylate GEP-1 characterized by DSC thermogram comprising an endotherm Peak at 236.78ºC, as shown in Figure 2.

In another embodiment, the present invention provides a crystalline Gepotidacin Mesylate GEP-1 characterized by TGA thermogram comprising no weight loss, as shown in Figure 3.

Crystalline Gepotidacin Mesylate GEP-1 was exposed to different stress conditions like exposure to relative humidity at room temperature, heating, grinding and open exposer and the product complies with the initial results and found to be stable.

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (instrument name Bruker D8 advance-Eco with lynex detector equipped with Cu source ?=1.58Å) measured using CuKa radiation. Methodology of X-ray diffraction is as follows:

Scanning Type: Continuous scan; Scan range: at least 3-40° 2theta; Step size: 0.8°; Time/Step: 0.05 sec; Divergence slit: V20; Rotation: 30 rpm

The Differential Scanning Calorimetry (DSC) thermogram is obtained on a Mettler-Toledo DSC3+. Methodology of DSC is as follows:

Nitrogen flow: 50.0 mL/min; Equilibrate: 25.0°C; Ramp: 10.0°C/min to 300.0°C.

The Thermogravimetric analyzer (TGA) thermogram is obtained on a Mettler-Toledo TGA2. Methodology of TGA is as follows:

Nitrogen flow: 50.0 mL/min; Equilibrate: 30.0°C; Ramp: 10.0°C/min to 300.0°C.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Preparation of crystalline Gepotidacin Mesylate GEP-1.

In a 25 mL round bottom flask, 120 mg Gepotidacin Mesylate dihydrate was dissolved in 2 mL 2-butanol at 80ºC, the obtained clear solution was added to 5 mL toluene at 80°C. The reaction mixture was stirred for 2-4hrs at 80°C temperature for recrystallization. Obtained solid was filtered and dried at 100°C under vacuum for 4-5 hours. Dried material was analyzed by DSC, TGA, & PXRD.

Example 2: Preparation of crystalline Gepotidacin Mesylate GEP-1.

In a 100 mL round bottom flask, 5gm Gepotidacin Mesylate dihydrate was dissolved in 2-Butanol (45.0ml) and methanol (5.0ml) mixture at 80°C and charged the above clear solution to toluene (100.0ml) at 80-90°C temperature. The reaction mixture was stirred for 30-60 mins. at 80-90°C temperature. The resulting solution was distilled partially until solid was observed. It was then cooled to 50-55°C and the precipitated solid was filtered and dried at 100°C under vacuum for 4-5hrs. Obtained material was analyzed by PXRD. ,CLAIMS:WE CLAIM:

1. A crystalline Form GEP-1 of Gepotidacin Mesylate, characterized by XRPD pattern having peaks at 9.5; 10.9; 17.3; 18.1 and 19.6 (± 0.2 degrees 2 theta).

2. The crystalline form according to claim 1, characterized by XRPD pattern having peaks at 14.9; 20.6; 21.7; 23.5 and 30.1 (± 0.2 degrees 2 theta).

3. The crystalline form according to claim 1, characterized by XRPD pattern having peaks at 3.7; 7.4; 9.5; 10.9; 12.7; 13.2; 14.0; 14.9; 15.6; 16.1; 16.7; 17.3; 18.1; 18.7; 19.1; 19.6; 20.1; 20.6; 21.0; 21.7; 22.4; 23.5; 24.3; 24.9; 25.4; 26.6; 26.9; 27.3; 28.8 and 30.1 (± 0.2 degrees 2 theta) as shown in Figure 1.

4. The crystalline form according to claim 1 characterized by DSC thermogram comprising an endotherm peak at 236.78 0C, as shown in Figure 2.

5. A process for the preparation of the crystalline Form GEP-1 of Gepotidacin Mesylate, which comprises;
a) dissolving Gepotidacin Mesylate or its hydrate in 2-butanol or mixture of 2-butanol and methanol to obtain a solution;
b) adding the solution of step a) to toluene;
c) stirring the above solution; and
d) obtaining the crystalline Gepotidacin Mesylate GEP-1.