DESC:
BACKGROUND OF THE INVENTION

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to the filing date of Indian Provisional Application No. IN 201941051586, filed on Dec 12, 2019;

FIELD OF THE DISCLOUSRE
The present disclosure relates to amorphous form of bedaquiline fumarate and process for its preparation thereof.
DESCRIPTION OF THE RELATED ART
Bedaquiline fumarate (trade name SIRTURO) is a medication used to treat tuberculosis. Bedaquiline is chemically known as (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-?1 represented by formula-1.

Bedaquiline and its preparation is described in U.S. Patent No 7,498,343 B2. Bedaquiline belongs to the group of quinoline derivatives that can be used as microbial inhibitors.

Bedaquiline fumarate preparation is disclosed in U.S. Patent No 8,5464,28 B2.

Crystalline Bedaquiline fumarate form I, II and III is disclosed in U.S. Patent No 1,01,96,360.

The inventors of the present disclosure have developed amorphous bedaquiline fumarate and its process for preparation thereof.

SUMMARY OF THE DISCLOSURE
A first aspect of the present invention is to provide amorphous bedaquiline fumarate.

Another aspect of the present invention is to provide a process for the preparation of amorphous bedaquiline fumarate, which comprises:
a) dissolving bedaquiline fumarate in a solvent; and
b) removing the solvent and isolating the amorphous bedaquiline fumarate.

BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure. 1 is an X-ray powder diffractogram of an amorphous bedaquiline fumarate.

DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The X-ray diffraction patterns of the amorphous Bedaquiline fumarate Figure-1 is provided herein were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ?/? configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0º-50.0°, 0.030° step size and 50 seconds step time.

The present disclosure relates to amorphous form of bedaquiline fumarate and process for its preparation thereof.

In one embodiment, the present invention provides a process for the preparation of amorphous bedaquiline fumarate, which comprises:
a) dissolving bedaquiline fumarate in a solvent; and
b) removing the solvent and isolating the amorphous bedaquiline fumarate.

Within the context of this embodiment of the present invention, bedaquiline fumarate is dissolved in a solvent.

Within the context of this embodiment, bedaquiline fumarate may be dissolved at temperature about 25±5 °C.

Within the context of this embodiment of the present invention, the solvent employed may include, organic solvents such as acetonitrile 1,4-dioxane, methanol, ethanol, propanol, dimethyl- formamide, dimethyl acetamide, tetrahydro furan, 2-methyl tetrahydro furan, dichloromethane, ethyl acetate, propyl acetate, dimethyl sulfoxide or mixtures thereof. In particularly useful embodiments of the present invention, the solvent is methanol.

Within the context of this embodiment of the present invention, removing of solvent can be done using any techniques in the art such as, decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation, lyophilization and spray drying. In particularly useful embodiments of the present invention, the solvent is removed by spray drying and distillation.

According to the present invention, the input bedaquiline fumarate is prepared by any prior-art process for example PCT publication No. WO2004011436A1.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Indicative stability:

In yet another embodiment, the physical stability of Bedaquiline fumarate Amorphous form was determined by storing the samples at 5±3°C, 25°C and 60% relative humidity (RH) and 40°C and 75% relative humidity (RH) conditions for three months and the samples were analyzed by

PXRD. The results are shown in below Table 1. The Bedaquiline fumarate Amorphous form was found to be physically stable at 5±3°C, 25°C and 60% relative humidity (RH) and at 40°C and 75% relative humidity (RH) conditions.
Table 1
Conditions/ Polymorph Bedaquiline fumarate Amorphous form
PXRD
at 5±3°C
Initial Amorphous form
3 months Stable
at 25°C/60% RH
Initial Amorphous form
3 months Stable
at 40°C/75% RH
Initial Amorphous form
3 months Stable

Solubility
The solubility of Bedaquiline fumarate Amorphous form and literature Form A were determined in water and different aqueous buffers of different pH at 37°C. The results are shown in the following Table 2. Amorphous form shows ~1.5 to 6 folds increase in buffer solubility whereas aqueous solubility is same in comparison with Literature Form A.
EXAMPLES
Example 1: Preparation of amorphous bedaquiline fumarate:

Bedaquiline Fumarate (5g) was dissolved in methanol (100mL) at 25±5°C. The resulting clear solution was filtered through hyflo bed (0.2g) to remove any undissolved particulates and the

solution was distilled out completely under vacuum at 40±5°C. Degassing for 60 minutes at 40±5 °C and cooled to 25±5 °C to yield bedaquiline fumarate amorphous form. Yield: 5g

Example 2: Preparation of amorphous bedaquiline fumarate:

Bedaquiline Fumarate (10g) was dissolved in methanol (200mL) at 25±5°C. The resulting clear solution was filtered through hyflo bed to remove any undissolved particulates and washed with methanol (20mL). The solution was subjected to spray-drying in a laboratory spray-dryer (Model: Buchi B-290) with feed rate of solution 5mL/minute and inlet temperature at 75°C to yield bedaquiline fumarate amorphous form. Yield: 7.4g
,CLAIMS:1. An amorphous bedaquiline fumarate
2. A process for the preparation of an amorphous bedaquiline fumarate, comprising the steps of:
a) dissolving bedaquiline fumarate in a solvent; and
b) removing the solvent and isolating the amorphous bedaquiline fumarate.
3. The process as claimed in claim 2, the solvent employed may include, organic solvents such as acetonitrile 1,4-dioxane, methanol, ethanol, propanol, dimethyl- formamide, dimethyl acetamide, tetrahydro furan, 2-methyl tetrahydro furan, dichloromethane, ethyl acetate, propyl acetate, dimethyl sulfoxide or mixtures thereof.
4. The process as claimed in claim 3, wherein the solvent is methanol.
5. The process as claimed in claim 2, wherein the isolation of amorphous bedaquiline fumarate is by distillation or spray drying.
6. The process as claimed in claim 5, wherein the spray drying is carried feeding the solution at a rate of 5mL/minute using inlet temperature at 75°C.