DESC:FORM 2

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

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

CRYSTALLINE HYDRATED FORMS OF APABETALONE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT NO.1, SURVEY NO.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
HYDERABAD, 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:
FIELD OF INVENTION
The present invention provides novel crystalline hydrated forms of Apabetalone, processes for their preparation and their use in pharmaceutical composition.
BACKGROUND OF THE INVENTION
Apabetalone (RVX-208), a first-in-class, small molecule that is a selective BET (bromodomain and extra-terminal) inhibitor and is chemically known as 2-[4-(2- hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one.

The structure of Apabetalone is given below:

Apabetalone is currently being studied in a Phase 3 trial, in high-risk CVD patients with type 2 DM. Apabetalone is disclosed in US 8,053,440, which is purified by using column chromatography.

US 10,752,595 discloses Apabetalone crystalline forms Form CS1 (anhydrate), Form CS2 (hydrate), Form CS4 (anhydrate), Form CS7 (anhydrate), Form CS8 (anhydrate), Form CS9 (anhydrate), Form CS11 (hydrate), Form CS13 (hydrate) and Form CS20 (AcOH solvate) using different solvents and drying conditions.

Considering the importance of Apabetalone and its use in cardiovascular treatment, nevertheless, besides the known forms of Apabetalone, there is still the need for a polymorph, which is stable as an API and during formulation and reproducible. The crystallization processes of the present invention involve the use of reagents that are less expensive and/or easier to handle and require smaller amounts to provide a higher yield of product with higher purity.

In view of the above, our inventors have developed novel crystalline hydrated forms of Apabetalone.

OBJECTIVE OF INVENTION
The main object of the present invention is to provide novel crystalline hydrated forms of Apabetalone.

Another object of the present invention is to provide a process of the preparation of crystalline hydrated forms of Apabetalone.

Yet another object of the present invention is to provide a pharmaceutical composition comprising the crystalline hydrated forms of Apabetalone.

SUMMARY OF THE INVENTION
The main embodiment of the present invention is to provide novel crystalline hydrated forms of Apabetalone.

Another embodiment of the present invention is to provide novel crystalline form of Apabetalone hydrate (Form APB-4), which is characterized by
• PXRD having 2? peaks at 4.4, 7.5, 11.6, 13.9 and 15.1 ± 0.2º 2?; (or)
• DSC thermogram is substantially as illustrated as in Figure 2; (or)
• TGA thermogram is substantially as illustrated in Figure 3.

Yet another embodiment of the present invention is to provide a process for the preparation of novel crystalline form of Apabetalone hydrate (Form APB-4), which comprises:
(i) dissolving Apabetalone in a solvent at a suitable temperature;
(ii) optionally, adding to a secondary solvent to the obtained solution at a suitable temperature;
(iii) cooling and filtering the solid;
(iv) drying and isolating novel crystalline form of Apabetalone hydrate (Form APB-4).

Yet another embodiment of the present invention is to provide novel crystalline form of Apabetalone hydrate (Form APB-8), which is characterized by
• PXRD having 2? peaks at 8.0, 9.2, 23.5, 25.1 and 26.4 ± 0.2° 2?, (or)
• DSC thermogram is substantially as illustrated as in Figure 4 (or)
• TGA thermogram is substantially as illustrated in Figure 5.

Yet another embodiment of the present invention is to provide a process for the preparation of novel crystalline form of Apabetalone hydrate (Form APB-8), which comprises:
(i) dissolving Apabetalone in a solvent at a suitable temperature;
(ii) optionally, adding to a secondary solvent to the obtained solution at a suitable temperature;
(iii) cooling and filtering the solid;
(iv) drying and isolating novel crystalline form of Apabetalone hydrate (Form APB-8).

Yet another embodiment of the present invention is to provide a pharmaceutical composition comprising the crystalline hydrated forms of Apabetalone.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: X-ray powder diffraction pattern of crystalline form of Apabetalone hydrate (Form APB-4).
Figure 2: DSC of crystalline form of Apabetalone hydrate (Form APB-4).
Figure 3: TGA of crystalline form of Apabetalone hydrate (Form APB-4).
Figure 4: X-ray powder diffraction pattern of crystalline form of Apabetalone hydrate (Form APB-8).
Figure 5: DSC of crystalline form of Apabetalone hydrate (Form APB-8).
Figure 6: TGA of crystalline form of Apabetalone hydrate (Form APB-8).
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel crystalline hydrates forms of Apabetalone, processes for their preparation and their use in pharmaceutical composition.
In a preferred embodiment, the hydrated form of the Apabetalone comprises crystalline form of Apabetalone hydrates Form APB-4 and Form APB-8.

The novel crystalline hydrated forms can be characterized by X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray powder diffraction pattern was measured on Bruker D8 advance-Eco with lynex detector equipped with Cu source (?=1.58Å). Scanning parameters: Scan type: Continuous scan; Scan range: 3-40°; Time/step: 0.8 sec; Step size: 0.05°; Divergence slit: V20; Rotation: 30 rpm or any equivalent X-ray powder diffractometer instrument.

In a preferred embodiment, the crystalline form of Apabetalone hydrate (Form APB-4) of the present invention has an XRPD profile substantially as shown in Figure 1.

In another preferred embodiment, the crystalline form of Apabetalone hydrate (Form APB-4) of the present invention has an XRPD peaks, in terms of 2?±0.2°, selected from 4.4, 7.5, 8.8, 9.7, 10.9, 11.6, 13.9, 15.1, 16.9.

In another preferred embodiment, the crystalline form of Apabetalone hydrate is characterized by a DSC thermogram having endothermic peaks at about 108.58°C, 230.01°C and exothermic peak at about 113.94°C.

In another preferred embodiment, the crystalline form of Apabetalone hydrate is characterized by a TGA thermogram having a weight loss of about 6.52%.

In yet another preferred embodiment, the present invention provides a process for the preparation of crystalline form of Apabetalone hydrate (Form APB-4), which comprises dissolving Apabetalone in a solvent selected from acid preferably propionic acid at a temperature of 70-95°C. Secondary solvent such as water is added to the above solution at 70-90ºC. The reaction mass is cooled to room temperature. The solid is filtered and washed with chilled water followed by dried to produce Form APB-4.
In yet another preferred embodiment, the present invention provides a process for the preparation of crystalline form of Apabetalone hydrate (Form APB-4), which comprises suspending propionic acid solvate of Apabetalone (Form APB-2) in water, heating the solution of step-i) at 80-95ºC; cooling and filtering the solid; washing the solid with isobutyl acetate, drying and isolating novel crystalline form of Apabetalone hydrate (Form APB-4).

In a preferred embodiment, the crystalline form of Apabetalone hydrate (Form APB-8) of the present invention has an XRPD profile substantially as shown in Figure 4.

In another preferred embodiment, the crystalline form of Apabetalone hydrate (Form APB-8) of the present invention has an XRPD peaks, in terms of 2?±0.2°, selected from 8.0, 9.2, 11.6, 12.4, 13.9, 23.5, 24.3, 25.1, 26.4 and 29.9.

In yet another preferred embodiment, the crystalline form of Apabetalone hydrate (Form APB-8) of the present invention is characterized by DSC having endothermic peaks at about 68.38°C, 230.04°C and exothermic peak at about 124.02°C.

In yet another preferred embodiment, the crystalline form of Apabetalone hydrate (Form APB-8) of the present invention is characterized by TGA thermogram having a weight loss of about 13.05%.

In yet another preferred embodiment, the present invention provides a process for the preparation of the crystalline Apabetalone hydrate (Form APB-8), which comprises dissolving Apabetalone in a solvent selected from dimethylformamide (DMF), diphenylformamide, at a temperature of 70-90°C. Secondary solvent such as water is added to the obtained solution at a temperature 35-45°C. The solid is filtered and washed with chilled water followed by dried to produce crystalline Apabetalone hydrate (Form APB-8).

In yet another preferred embodiment, the present invention provides a process for the preparation of the crystalline Apabetalone hydrate (Form APB-8), which comprises dissolving Apabetalone in a solvent selected from ethane, propane, butanes, nitromethane, nitroethane, nitropropanae and water at a temperature of 70-90°C. Secondary solvent such as water is added to the obtained solution at a temperature 35-45°C. The solid is filtered and washed with chilled water followed by dried to produce crystalline Apabetalone hydrate (Form APB-8).

In yet another preferred embodiment, the present invention provides a pharmaceutical composition comprising novel crystalline hydrated forms of Apabetalone. The process for the preparation of the pharmaceutical composition comprises addition of the novel crystalline hydrated forms of Apabetalone and a pharmaceutically acceptable excipient.

The “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

Apabetalone used in this invention is prepared according to the process disclosed in the literature. The Apabetalone used in this invention is a crude Apabetalone or a crystalline form of Apabetalone or an amorphous form of Apabetalone.
The following example(s) 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.

Example-1: Preparation of crystalline form of Apabetalone hydrate (Form APB-4):
Apabetalone was (50mg) dissolved in propionic acid (0.8ml) at 80-85°C. Obtained solution was added to water at 85°C, stirred for 15-20 mins then cooled to RT. Resulting solid was filtered and washed with chilled water (1ml) followed by suck dried under nitrogen atmosphere for 5min’s. Further material was dried at 85°C for 3hrs under vacuum to afford crystalline form of Apabetalone hydrate (Form APB-4). Dried material is analyzed by PXRD as shown in Figure-1.

Example-2: Preparation of crystalline form of Apabetalone hydrate (Form APB-4):
Water (1.5ml) was added to Apabetalone propionic acid solvate (50mg) and heated to 90-95°C, stirred for 5-10 minutes and cooled to 5°C. Resulting solid was filtered and washed with chilled isobutyl acetate (0.5ml) followed by suck dried under nitrogen atmosphere for 5min’s to afford crystalline form of Apabetalone hydrate (Form APB-4). Dried material is analyzed by PXRD as shown in Figure-1.

Example-3: Preparation of crystalline form of Apabetalone hydrate (Form APB-8)
Apabetalone (50mg) was dissolved in DMF (0.3ml) at 80-85°C. Obtained solution was added to water at 40°C then stirred for 1-2 hrs. Resulting solid was filtered and washed with chilled water (1ml) followed by suck dried under nitrogen atmosphere for 20 min’s to afford crystalline form of Apabetalone hydrate (Form APB-8). Dried material is analyzed by PXRD as shown in Figure-4.

Example-4: Preparation of crystalline form of Apabetalone hydrate (Form APB-8)
Apabetalone (50mg) was dissolved in mixture of nitromethane and water (0.8 and 0.2 ml) at 80-85°C. Obtained solution was cooled to 0-5°C then stirred for 1-2 hrs. Resulting solid was filtered and washed with chilled water (0.5ml) followed by suck dried under nitrogen atmosphere for 20 min’s to afford crystalline form of Apabetalone hydrate (Form APB-8). Dried material is analyzed by PXRD as shown in Figure-4. ,CLAIMS:WE CLAIM:
1. A novel crystalline form of Apabetalone hydrate (Form APB-4), which is characterized by:
• PXRD having 2? peaks at 4.4, 7.5, 11.6, 13.9 and 15.1 ± 0.2º 2?; (or)
• DSC thermogram is substantially as illustrated as in Figure 2; (or)
• TGA thermogram is substantially as illustrated in Figure 3.

2. The crystalline form as claimed in claim 1, is further characterized by PXRD having 2? peaks at 8.8, 9.7, 10.9 and 16.9 ± 0.2º 2?

3. A process for the preparation of the crystalline form of Apabetalone hydrate (Form APB-4) as claimed in claim 1, comprises:
(i) dissolving Apabetalone in a solvent at a suitable temperature;
(ii) optionally, adding to a secondary solvent to the obtained solution at a suitable temperature;
(iii) cooling and filtering the solid;
(iv) drying and isolating novel crystalline form of Apabetalone hydrate (Form APB-4).

4. A novel crystalline form of Apabetalone hydrate (Form APB-8), which is characterized by:
• PXRD having 2? peaks at 8.0, 9.2, 23.5, 25.1 and 26.4 ± 0.2° 2?; (or)
• DSC thermogram is substantially as illustrated as in Figure 5; (or)
• TGA thermogram is substantially as illustrated in Figure 6.

5. The crystalline form as claimed in claim 4, is further characterized by PXRD having 2? peaks at 11.6, 12.4, 13.9, 24.3, and 29.9 ± 0.2º 2?.

6. A process for the preparation of the crystalline form of Apabetalone hydrate (Form APB-8) as claimed in claim 4, comprises:
(i) dissolving Apabetalone in a solvent at a suitable temperature;
(ii) optionally, adding to a secondary solvent to the obtained solution at a suitable temperature;
(iii) cooling and filtering the solid;
(iv) drying and isolating novel crystalline form of Apabetalone hydrate (Form APB-8).

7. A pharmaceutical composition comprising the crystalline forms as claimed in claims 1 and 4, and at least one pharmaceutically acceptable excipient.