DESC:FORM 2

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

COMPLETE SPECIFICATION

(Section 10 and Rule 13)

CRYSTALLINE 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 forms of Apabetalone or solvates thereof, a process for the preparation thereof and a pharmaceutical composition containing crystalline forms of Apabetalone or solvates thereof.
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.

Apabetalone is the first and only chronic BET inhibitor selective for the second bromodomain (BD2) within the BET proteins and is currently being studied in a Phase 3 trial, in high-risk CVD patients with type 2 DM.

The structure of Apabetalone is shown as follows:

Formula I

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 solvents 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 forms of Apabetalone.

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

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

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

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

An embodiment of the present invention is to provide novel crystalline form of Apabetalone (Form APB-5), which is characterized by:
• PXRD having 2? peaks at 5.8, 9.1, 10.3 12.6 and 26.7 ± 0.2° 2?; (or)
• DSC thermogram is substantially as illustrated as in Figure 2; (or)
• TGA thermogram is substantially as illustrated in Figure 3.

Another embodiment of the present invention is to provide a process for the preparation of the novel crystalline form of Apabetalone (Form APB-5), which comprises:
(i) dissolving crystalline propionic acid solvate of Apabetalone (Form APB-2) in a solvent at a suitable temperature;
(ii) cooling and filtering the solid;
(iii) drying to obtain the novel crystalline form of Apabetalone (Form APB-5).

Yet another embodiment of the present invention is to provide novel crystalline form of Apabetalone (Form APB-12), which is characterized by
• PXRD having 2? peaks at 5.6, 8.0, 11.4, 12.6 and 16.0 ± 0.2º 2?; (or)
• DSC thermogram is substantially as illustrated as in Figure 5; (or)
• TGA thermogram is substantially as illustrated in Figure 6.

Yet another embodiment of the present invention is to provide a process for the preparation of novel crystalline form of Apabetalone (Form APB-12), 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) drying and isolating novel crystalline form of Apabetalone (Form APB-12).

Yet another embodiment of the present invention is to provide a crystalline propionic acid solvate of Apabetalone (Form APB-2), which is characterized by
• PXRD having 2? peaks at 4.0, 8.8, 10.7, 12.7 and 14.4 ± 0.2° 2?; (or)
• DSC thermogram is substantially as illustrated as in Figure 8; (or)
• TGA thermogram is substantially as illustrated in Figure 9.

Yet another embodiment of the present invention is to provide a process for the preparation of crystalline propionic acid solvate of Apabetalone (Form APB-2), which comprises:
(i) dissolving Apabetalone in propionic acid at suitable temperature;
(ii) cooling and filtering the solid;
(iii) washing with a solvent;
(iv) drying the solid to obtain the crystalline propionic acid solvate of Apabetalone (Form APB-2).

Yet another embodiment of the present invention is to provide a pharmaceutical composition comprising novel crystalline forms viz., crystalline form of Apabetalone (Form APB-5), crystalline form of Apabetalone (Form APB-12), and crystalline propionic acid solvate of Apabetalone (Form APB-2).

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: X-ray powder diffraction pattern of crystalline form of Apabetalone (Form APB-5).
Figure 2: DSC of crystalline form of Apabetalone (Form APB-5).
Figure 3: TGA of crystalline form of Apabetalone (Form APB-5).
Figure 4: X-ray powder diffraction pattern of crystalline form of Apabetalone (Form APB-12).
Figure 5: DSC of crystalline form of Apabetalone (Form APB-12).
Figure 6: TGA of crystalline form of Apabetalone (Form APB-12).
Figure 7: X-ray powder diffraction pattern of crystalline propionic acid solvate of Apabetalone (Form APB-2).
Figure 8: DSC of crystalline propionic acid solvate of Apabetalone (Form APB-2).
Figure 9: TGA of crystalline propionic acid solvate of Apabetalone (Form APB-2).

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel crystalline forms of Apabetalone or solvates thereof and processes for their preparation and their use in pharmaceutical composition.

In a preferred embodiment, the crystalline forms may be substantially anhydrous, a solvate, which are stable and do not covert to any other forms.

The novel crystalline 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 (Form APB-5) of the present invention has an XRPD profile substantially as shown in Figure 1.

The crystalline form of Apabetalone (Form APB-5) of the present invention has XRPD peaks, in terms of 2? ±0.2°, selected from 5.8, 8.0, 9.1, 10.3, 11.0, 12.6, 17.0, 20.7, 23.8 and 26.7.

The crystalline form of Apabetalone (Form APB-5) of the present invention is characterized by a DSC having a peak having endothermic peak at about 229.33°C.

The crystalline form of Apabetalone (Form APB-5) of the present invention is characterized by a TGA thermogram having a weight loss of about 1.09%.

In yet another preferred embodiment, the crystalline form of Apabetalone (Form APB-5) of the present invention is substantially anhydrous.

In yet another preferred embodiment, the present invention provides a process for the preparation of crystalline form of Apabetalone (Form APB-5). The process comprising dissolving crystalline propionic acid solvate of Apabetalone (Form APB-2) in a solvent selected from esters preferably ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate at suitable temperature ranges from 60?C to 115?C, cooling the reaction mass at RT to -20?C to obtain a solid which is filtered & dried to obtain the crystalline form of Apabetalone (Form APB-5).

The crystalline Form APB-5 obtained by the above process has good long-term stability, which can ensure that the quality of the drug will be affected as polymorphic transition will not occur in the process of preparation, transportation, and storage.

In another preferred embodiment, the crystalline form of Apabetalone (Form APB-12) of the present invention has an XRPD profile substantially as shown in Figure 4.

In another preferred embodiment, the crystalline form of Apabetalone (Form APB-12) of the present invention has an XRPD peaks, in terms of 2?±0.2°, selected from 5.6, 8.0, 11.4, 12.6, 12.9, 14.3, 16.0, 19.5, 20.5 and 21.3.

In another preferred embodiment, the crystalline form of Apabetalone (Form APB-12) of the present invention is characterized by a DSC having a peak having endothermic peak at about 230.61°C.

In another preferred embodiment, the crystalline form of Apabetalone (Form APB-12) of the present invention is characterized by a TGA thermogram having a weight loss of about 1.48%.

In yet another preferred embodiment, the crystalline form of Apabetalone (Form APB-12) of the present invention is substantially anhydrous.

In yet another preferred embodiment, the present invention provides a process for the preparation of crystalline form of Apabetalone (Form APB-12), which comprises dissolving Apabetalone in a solvent selected from acid preferably propionic acid at suitable temperature of 65-90ºC to obtain a solution, which is added to a secondary solvent selected from methyl tert-butyl ether (MTBE), ethyl tert-butyl ether (ETBE), and diisopropyl ether at suitable temperature of RT to 50°C to obtain a solid. The solid is filtered and dried to obtain anhydrous crystalline Apabetalone (Form APB-12).

In another preferred embodiment, the crystalline propionic acid solvate of Apabetalone (Form APB-2) of the present invention has an XRPD profile substantially as shown in Figure 7.

The crystalline propionic acid solvate of Apabetalone (Form APB-2) of the present invention has XRPD peaks, in terms of 2?±0.2°, selected from 4.0, 4.8, 7.2, 8.8, 10.7, 11.7, 12.7, 14.4, and 21.7.

The crystalline propionic acid solvate of Apabetalone (Form APB-2) of the present invention is characterized by a DSC having a peak having endothermic peaks at about 105.37°C, 127.04°C, 136.92°C and 230.28°C.

The crystalline propionic acid solvate of Apabetalone (Form APB-2) of the present invention is characterized by TGA thermogram having a weight loss of about 20.58%.

In yet another preferred embodiment, the present invention provides a process for the preparation of crystalline propionic acid solvate of Apabetalone (Form APB-2). The process comprises, dissolving Apabetalone in propionic acid at suitable temperature ranges from 60?C to 115?C, followed by cooling the reaction mass at RT to 0?C to obtain a solid. The solid is washed with a secondary solvent selected from ketone preferably acetone or methyl ethyl ketone and dried the solid to obtain the crystalline propionic acid solvate of Apabetalone (Form APB-2).

In yet another preferred embodiment, the present invention provides a pharmaceutical composition comprising crystalline forms of Apabetalone or its solvates. The process for the preparation of the pharmaceutical composition comprises addition of the crystalline 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.

EXAMPLES:
EXAMPLE-1: Preparation of crystalline form of Apabetalone (Form APB-5):
Apabetalone propionic acid solvate (50mg) was dissolved in isobutyl acetate (3ml) at 85-90°C, stirred for 5-10 minutes and cooled to -8°C to -5°C. The 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 (Form APB-5). Dried material is analyzed by PXRD as shown in Figure-1.

Example-2: Preparation of crystalline form of Apabetalone (Form APB-12):
Apabetalone (50mg) was dissolved in propionic acid (0.1ml) at 80-85°C. Obtained solution was added to MTBE at 40°C, then stirred for 25-30 mins. Resulting solid was filtered and washed with MTBE (0.5ml) followed by suck dried under nitrogen atmosphere for 5-10 min’s. Further material was dried at 65°C for 3hr under vacuum to afford crystalline form of Apabetalone (Form APB-12). Dried material is analyzed by PXRD as shown in Figure-4.

EXAMPLE-3: Preparation of crystalline propionic acid solvate of Apabetalone (Form APB-2):
Apabetalone (100mg) was dissolved in propionic acid (0.8ml) at 85-90°C, stirred for 5-10 minutes and cooled to RT. The Obtained solid was filtered and washed with chilled acetone (0.5ml) followed by suck dried under nitrogen atmosphere for 5min’s. Further, the material was dried at 35±5°C under vacuum for 3-4hr’s to afford crystalline propionic acid solvate of Apabetalone (Form APB-2). Dried material is analyzed by PXRD as shown in Figure-7. ,CLAIMS:WE CLAIM:
1. A novel crystalline form of Apabetalone (Form APB-5), which is characterized by;
• PXRD having 2? peaks at 5.8, 9.1, 10.3 12.6 and 26.7 ± 0.2° 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 8.0, 11.0, 17.0, 20.7 and 23.8 ± 0.2º 2?.

3. A process for the preparation of the crystalline form of Apabetalone (Form APB-5) as claimed in claim 1, comprises:
(i) dissolving crystalline propionic acid solvate of Apabetalone (Form APB-2) in a solvent at a suitable temperature;
(ii) cooling and filtering the solid;
(iii) drying to obtain the novel crystalline form of Apabetalone (Form APB-5).

4. A novel crystalline form of Apabetalone (Form APB-12), which is characterized by;
• PXRD having 2? peaks at 5.6, 8.0, 11.4, 12.6 and 16.0 ± 0.2º 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 12.9, 14.3, 19.5, 20.5 and 21.3 ± 0.2º 2?.

6. A process for the preparation of the crystalline form of Apabetalone (Form APB-12) 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) drying and isolating novel crystalline form of Apabetalone (Form APB-12).

7. A novel crystalline propionic acid solvate of Apabetalone (Form APB-2), which is characterized by;
• PXRD having 2? peaks at 4.0, 8.8, 10.7, 12.7 and 14.4 ± 0.2° 2?; (or)
• DSC thermogram is substantially as illustrated as in Figure 8; (or)
• TGA thermogram is substantially as illustrated in Figure 9.

8. The crystalline form as claimed in claim 7, is further characterized by PXRD having 2? peaks at 4.8, 7.2, 11.7 and 21.7.

9. A process for the preparation of the crystalline form of Apabetalone (Form APB-2) as claimed in claim 7, comprises:
(i) dissolving Apabetalone in propionic acid at suitable temperature;
(ii) cooling and filtering the solid,
(iii) washing with a solvent;
(iv) drying the solid to obtain the crystalline propionic acid solvate of Apabetalone (Form APB-2).

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