Claims:WE CLAIM:

1. Crystalline form “P” of Bempedoic acid.

2. A crystalline form “P” of Bempedoic acid as claimed in claim 1, characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflection at about 10.2, 17.2, 17.4, 20.2 and 21.7 ±0.2 degrees 2θ.

3. A crystalline form “P” of Bempedoic acid as claimed in claim 2 and 3, further characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflections at about 5.0, 10.2, 11.6, 13.6, 14.3, 15.4, 17.2, 17.4, 18.1, 18.6, 19.4, 20.2, 20.6, 21.7, 22.4, 23.0, 24.5, 25.6, 26.1 and 27.4 ±0.2 degrees 2θ.

4. A crystalline form “P” of Bempedoic acid as claimed in claim 1, having a powder X-ray powder diffraction pattern substantially in accordance with Figure-1.

5. A crystalline form “P” of Bempedoic acid as claimed in claim 1, having a differential scanning calorimetry (DSC) onset at 87.99ºC as depicted in Figure 2.

6. A crystalline form “P” of Bempedoic acid as claimed in claim 1, Infra-red (IR) spectrum having peak reflections at about 3796, 3437, 3342, 3132, 3035, 2990, 2884, 2719, 2661, 2586, 2347, 2134, 1919, 1842, 1713, 1690, 1676, 1582, 1570, 1510, 1477, 1392, 1297, 1190, 1095, 996, 896, 795, 665, 598 and 484, as depicted in Figure 3.

7. A purification process for preparing crystalline form “P” of Bempedoic acid comprising:

a. Crude Bempedoic acid was dissolved in ester solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b), and
d. isolating the pure Bempedoic acid.

8. The process as claimed in claim 7 step b), wherein the heating reaction is carried out at 50-55º C for 15-20 mins.

9. The process as claimed in claim 7, wherein the ester solvent is selected from group consisting of ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and propyl acetate.

10. The crystalline form “P” of Bempedoic acid as claimed in claim 1, having particle size distribution D90 less than about 250 μm.

, Description:CRYSTALLINE FORM “P” OF BEMPEDOIC ACID

FIELD OF THE INVENTION

The present invention relates to crystalline form “P” of Bempedoic acid. The present invention also relates to a purification process for preparing crystalline form “P” of Bempedoic acid with high purity and yield.

BACKGROUND OF THE INVENTION

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia (high blood cholesterol levels). Bempedoic acid blocks an enzyme in the liver called adenosine triphosphate citrate lyase, which is involved in making cholesterol.

In US, Bempedoic acid is indicated for the treatment of hypercholesterolemia in combination with diet and the highest tolerated statin therapy in adults with heterozygous familial hypercholesterol emia or with established atherosclerotic cardiovascular disease, who need additional lowering of LDL cholesterol. In EP, Bempedoic acid is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL C goals with the maximum tolerated dose of a statin; or alone or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated.

Bempedoic acid is chemically known as 8-hydroxy-2,2,14,14­tetramethyl-pentadecane dioic acid of formula (I) has the following structure.

Bempedoic acid is reported in US 7335799 by Esperion Therapeutics Inc. The synthetic process for Bempedoic acid is explained and not disclosed about polymorphism in US ‘799.

EP 3666750 A1 of Sandoz discloses crystalline form of Bempedoic acid and its process for preparation, which comprises crude Bempedoic acid was purified via column chromatography (eluent iPr2O-Et2O) and recrystallized from iPr2O to give crystalline Bempedoic acid. According to EP ‘750 patent the crystalline form of Bempedoic acid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 10.3, 15.6, 17, 17.3, 17.5, 18, 20.3, 21.1, 21.8, 27.6 and 29.8 ±0.2 degrees 2θ.

IPCOM000254434D of Egis Pharmaceuticals discloses crystalline form of Bempedoic acid and it’s process for preparation, which comprises crude Bempedoic acid was added to 2- to 8- fold excess of warm diisopropyl ether and stirred until complete dissolution, then the solution was left to cool and the title compound was solidified. The white-almost white crystals were filtered off and adequately dried in vacuo to obtain crystalline form of Bempedoic acid onset at 83°C. According to the IPCOM000254434D, the crystalline form of Bempedoic acid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 5.1, 10.2, 11.6, 13.6, 14.4, 15.5, 17, 17.2, 17.5, 17.9, 18.7, 19.6, 20.3, 21.0, 21.7, 22.5, 23.5, 24.6, 26.2, 27.6, 28.5, and 29.8 ±0.2 degrees 2θ.

IN 201821049982 of Lupin discloses crystalline form of Bempedoic acid and it’s process for preparation, which comprises crude Bempedoic acid was dissolved in diisopropyl ether, reaction mass was stirred at 60°C for 3 hr. Reaction mass was cooled to room temperature, Filtered the reaction mass and dried at 40°C to obtained crystalline Bempedoic acid onset at 87.72ºC. According to the IN ‘982 patent the crystalline form of Bempedoic acid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at 5.0, 10.2, 11.6, 13.5, 14.3, 15.5, 17.3, 17.4, 17.8, 18.6, 19.4, 20.2, 20.9, 21.7, 22.4, 23.4,24.5 and 29.7 ±0.2 degrees 2θ.

The object of the present invention to purification process of Bempedoic acid.

Bempedoic acid exists in a crystalline form and the crystalline form having distinct crystal structures and physical properties. Consequently, there is an ongoing search for a new polymorphic form of drug, which may provide improved performance thereof.

In view of the foregoing, the present inventors have provided purification process of Bempedoic acid and Crystalline Form “P” of Bempedoic acid with commercially suitable reaction conditions with high yield and purity. The process is simple, efficient more economical and eco-friendly.

SUMMARY OF THE INVENTION

The present invention relates to crystalline form “P” of Bempedoic acid. The present invention also relates to a purification process for preparing Bempedoic acid with high purity and yield.

In one aspect of the present invention, it provides a crystalline form “P” of Bempedoic acid characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about
10.2, 17.2, 17.4, 20.2 and 21.7 ±0.2 degrees 2θ.

In another aspect of the present invention, it provides a purification process for the preparation of crystalline form “P” of Bempedoic acid, comprising:

a. Crude Bempedoic acid was dissolved in ester solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b), and
d. isolating the pure Bempedoic acid.

In yet another aspect of the present invention, crystalline form “P” of Bempedoic acid having particle size distribution D90 less than about 250 μm.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: X-ray powder diffraction (PXRD) crystalline form “P” of Bempedoic acid.

Figure 2: Differential scanning calorimetry (DSC) crystalline form “P” of Bempedoic acid.

Figure 3: Infra-red (IR) spectra crystalline form “P” of Bempedoic acid.
DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to crystalline form “P” of Bempedoic acid. The present invention also relates to a purification process for preparing crystalline form “P” of Bempedoic acid with high purity and yield.

In one embodiment of the present invention, the crystalline form “P” of Bempedoic acid is characterized by X-Ray powder diffraction spectrum as depicted in Figure 1.

In an embodiment of the present invention provides the crystalline form “P” of Bempedoic acid characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 10.2, 17.2, 17.4, 20.2 and 21.7 ±0.2 degrees 2θ.

According to the embodiment of the crystalline form “P” of Bempedoic acid is further characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.0, 10.2, 11.6, 13.6, 14.3, 15.4, 17.2, 17.4, 18.1, 18.6, 19.4, 20.2, 20.6, 21.7, 22.4, 23.0, 24.5, 25.6, 26.1 and 27.4 ±0.2 degrees 2θ.

According to the embodiment of the present invention, the crystalline form “P” of Bempedoic acid differential scanning calorimetry (DSC) onset at 87.99ºC as depicted in Figure 2.

According to the embodiment of the present invention, the crystalline form “P” of Bempedoic acid Infra-red (IR) spectrum having peak reflections at about 3796, 3437, 3342, 3132, 3035, 2990, 2884, 2719, 2661, 2586, 2347, 2134, 1919, 1842, 1713, 1690, 1676, 1582, 1570, 1510, 1477, 1392, 1297, 1190, 1095, 996, 896, 795, 665, 598 and 484, as depicted in Figure 3.

Another embodiment of the present invention provides a purification for the preparation of crystalline form “P” of Bempedoic acid, comprising:

a. Crude Bempedoic acid was dissolved in ester solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b), and
d. isolating the pure Bempedoic acid.

According to the embodiment of the present invention, the crude of Bempedoic acid crude material is dissolved in ethyl acetate at 25-30°C. The reaction mass temperature was raised to 50-55°C for 15-20 min to get clear solution, it was cooled to 5-10°C and filtered. Activated charcoal was added to reaction mass at 50-55°C for 25-30 min. It was filtered through hyflo bed and filtrate was cooled to 15-20°C. The wet material was dried at 45-50°C for 8 hrs to get pure Bempedoic acid

According to the embodiment of the present invention, the ester solvent is selected from group consisting of ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and propyl acetate and water thereof.

Another embodiment of the present invention provides, crystalline form “P” of Bempedoic acid having particle size distribution D90 10 to 250 μm.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

EXAMPLES

Example-1:
Purification of Bempedoic acid:

100 gm (0.29 moles) of Bempedoic acid crude material and ethyl acetate (300 ml) were taken at 25-30°C. The reaction mass temperature was raised to 50-55°C and the reaction mass was maintained for 15-20 min at 50-55°C to get clear solution. The reaction mass was cooled to 5-10°C and the precipitated solid was filtered at 5-10°C and unload wet material.
The wet material and ethyl acetate (180 ml) were taken at 25-30°C. The reaction mass temperature was raised to 50-55°C and the reaction mass was maintained for 15-20 min at 50-55°C to get clear solution. Activated charcoal (5g) was added to reaction mass and maintained for 25-30 min at 50-55°C. The reaction mass was filtered through hyflo bed, filtrate was cooled to 15-20°C and the precipitated solid was filtered at 15-20°C. The wet material was dried at 45-50°C for 8 hrs to get pure Bempedoic acid.

Yield: 63 gm
HPLC Purity: 99.8%.

Example-2:
Purification of Bempedoic acid:

100 gm (0.29 moles) of Bempedoic acid crude material and ethyl acetate (200 ml) were taken at 25-30°C. The reaction mass temperature was raised to 70-75°C and the reaction mass was maintained for 30 min at 70-75°C to get clear solution. The reaction mass was cooled to 25-30°C and the precipitated solid was filtered at 25-30°C and unload wet material.
The wet material and ethyl acetate (180 ml) were taken at 25-30°C. The reaction mass temperature was raised to 70-75°C and the reaction mass was maintained for 30 min at 70-75°C to get clear solution. Activated charcoal (5 gm) was added to reaction mass and maintained for 25-30 min at 70-75°C. The reaction mass was filtered through hyflo bed, filtrate was cooled to 20-25°C and the precipitated solid was filtered at 20-25°C. The wet material was dried at 45-50°C for 8 hrs to get pure Bempedoic acid.
Yield: 65 gm
HPLC Purity: 99.7%.

Example-3:

Purification of Bempedoic acid

100 gm (0.29 moles) of Bempedoic acid crude material and ethyl acetate (400 ml) were taken at 25-30°C. The reaction mass temperature was raised to 45-50°C and the reaction mass was maintained for 30 min at 45-50°C to get clear solution. The reaction mass was cooled to 0-5°C and the precipitated solid was filtered at 0-5°C and unload wet material.
The wet material and ethyl acetate (300 ml) were taken at 25-30°C. The reaction mass temperature was raised to 45-50°C and the reaction mass was maintained for 30 min at 45-50°C to get clear solution. Activated charcoal (5 gm) was added to reaction mass and maintained for 25-30 min at 45-50°C. The reaction mass was filtered through hyflo bed, filtrate was cooled to 0-5°C and the precipitated solid was filtered at 0-5°C. The wet material was dried at 45-50°C for 8hrs to get pure Bempedoic acid.

Yield: 62 gm
HPLC Purity: 99.9%.