DESC:FIELD OF THE INVENTION
The present invention relates to novel crystalline forms of quinolone based compounds and process for the preparation thereof, use thereof and pharmaceutical composition comprising the same.
BACKGROUND OF THE INVENTION
The invention is related to novel crystalline forms of quinolone based compounds.
WO2014102818 discloses quinolone derivatives including (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydro quinoline-3-carbonyl)glycine compound of Formula (I), as Hypoxia-inducible factor (HIF) inhibitors having utility in any disease state where ischemia hypoxia and/or anemia plays a role.

Formula (I)
U.S. patent application no. 2019/0359574 discloses process for preparation of quinolone compounds including the compound of Formula (I) and a crystalline form thereof.
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, IR etc. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form.
The discovery of new polymorphic forms is a continuing goal of formulators. The new polymorphs may be advantageous for dosage form development and enhancing bioavailability owing to the altered physiochemical properties. Some form may turn out to be more efficacious. The present invention is a step forward in this direction and provides new crystalline forms of formula (I) and process for its preparation. As an active pharmaceutical substance it is also required that the pharmaceutical substance should also meet the necessities of using it for the preparation of a pharmaceutical composition and so the compound should exhibit desired physicochemical properties to be incorporated in a pharmaceutical composition. The polymorphic form of the present invention can be used to prepare suitable pharmaceutical composition.
New crystalline forms of the present invention may exist in four different substantially crystalline forms can be designated as Form A, Form B, Form C and Form D.
EMBODIMENT(S) OF THE INVENTION
In an embodiment, the present invention provides crystalline forms of formula (I).
In one embodiment, the present invention provides crystalline Form A of compound of formula (I) and process for preparation thereof, which can be further characterized by its powder X-ray diffraction pattern.
In another embodiment, the present invention provides crystalline Form B of compound of formula (I) and process for preparation thereof, which can be further characterized by its powder X-ray diffraction pattern.
In another embodiment, the present invention provides crystalline Form C of compound of formula (I) and process for preparation thereof, which can be further characterized by its powder X-ray diffraction pattern.
In another embodiment, the present invention provides crystalline Form D of compound of formula (I) and process for preparation thereof, which can be further characterized by its powder X-ray diffraction pattern.
In a further embodiment, the present invention provides a pharmaceutical composition comprising crystalline form A, crystalline form B, crystalline form C and crystalline form D of compound of Formula (I) and pharmaceutically acceptable excipients.
In yet another embodiment the present invention provides a pharmaceutical composition comprising crystalline form A, crystalline form B, crystalline form C and crystalline form D of compound of Formula (I) useful in the treatment of conditions associated with anemia.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
FIG.1: Powder X-ray diffraction (XRD) pattern of crystalline form A of compound of Formula (I) as prepared in example 1.
FIG.2: Powder X-ray diffraction (XRD) pattern of crystalline form B of compound of Formula (I) as prepared in example 2.
FIG.3: Powder X-ray diffraction (XRD) pattern of crystalline form C of compound of Formula (I) as prepared in example 3.
FIG.4: Powder X-ray diffraction (XRD) pattern of crystalline form D of compound of Formula (I) as prepared in example 4.
DETAILED DESCRIPTION OF THE INVENTION
The terms ‘dissolving’, ‘contacting’, ‘slurring’, ‘stirring’, ‘mixing’ are interchangeable terms and doesn’t affect the scope of the present invention.
The terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable, and include but not specifically limited to decantation, extraction, filtration, evaporation, lyophilisation, spray drying, crystallization, recrystallization or chromatographic operations.
The term “pharmaceutically acceptable” as used herein means useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and is acceptable for veterinary or human pharmaceutical use.
The term "pharmaceutical composition" as used herein means a drug product comprising the active ingredient(s) & pharmaceutically acceptable excipient(s), as well as any product, which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients including an active ingredient.
In one general aspect there is provided crystalline forms of compound of formula (I).
Compound of formula (I) required for the preparation of new crystalline forms can be synthesized by the process disclosed in US patent no. US 10899713.
In one embodiment, the present invention provides crystalline Form A of compound of formula (I) which can be further characterized by its powder X-ray diffraction pattern (PXRD) as depicted in Fig. 1.
In another embodiment there is provided a process for the preparation of Form A which comprises,
a) dissolving compound of formula (I) in a suitable solvent under suitable condition;
b) isolating the resulting solid as crystalline Form A.
In an embodiment, compound of formula (I) is soluble or partially soluble in suitable solvents. In such embodiment the suitable solvent used in step (a) is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, cyclohexanone, diisobutyl ketone, diacetone alcohol, isophorone or mixtures thereof. Most preferred solvent is acetone.
In one embodiment, the crystalline form A of the compound of formula (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2?±0.2° at 10.2, 11.1and 26.8.
In another embodiment, there is provided a crystalline form A of compound of Formula25 (I) characterized by X-ray powder diffraction pattern having peaks expressed in degrees 2?±0.2° at 9.4, 10.2, 11.1, 14.5, 18.2, 18.8, 21.0, 21.5, 22.7 and 28.1.
In another embodiment there is provided Form B of compound of formula (I), which can be further characterized by its powder X-ray diffraction pattern (PXRD) as depicted in Fig. 2.
In another embodiment there is provided a process for the preparation of Form B, which comprises,
a) dissolving compound of formula (I) in a suitable solvent under suitable condition;
b) isolating the resulting solid as crystalline Form B.
The suitable solvent used in step (a) is selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, di-tert-butyl ether, di(propylene glycol) methyl ether, dibutyl ether,diethyl ether, diisopropyl ether, dimethoxyethane, dimethoxymethane, 1,4-Dioxane, ethyl tert-butyl ether, methyl tert-butyl ether or mixtures thereof. Most preferred solvent is tetrahydrofuran.
In one embodiment, the crystalline form B of the compound of Formula (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2?±0.2° at 8.0, 8.9, and 25.6.
In another embodiment, there is provided a crystalline form B of compound of Formula (I) characterized by X-ray powder diffraction pattern having peaks expressed in degrees 2?±0.2° at 5.7, 8.0, 8.9, 10.1, 10.7, 11.4, 16.2, 19.2, 21.4, 22.0, 22.7, 25.6, 26.6, 26.8 and 29.6.
In another embodiment there is provided Form C of compound of formula (I), which can be further characterized by its powder X-ray diffraction pattern (PXRD) as depicted in Fig. 3.
In another embodiment there is provided a process for the preparation of Form C which comprises,
a) dissolving compound of Formula (I) in a suitable solvent mixture to obtain a first reaction mixture;
b) adding suitable base to the mixture obtained from step (a);
c) adding suitable acid solution to the mixture obtained from step (b);
d) isolating the resulting precipitated solid as crystalline Form C.
The suitable solvent mixture used in step (a) is selected from a mixture of alcohol and water.
In general, the alcohol is selected from a group comprising methanol, ethanol, isopropyl alcohol, butanol, isobutanol, 2-methyl-1-butanol or mixtures thereof. Most preferred solvent is methanol.
The suitable base used in step (b) is selected from lithium hydroxide, Sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, Barium hydroxide or mixtures thereof. Most preferred is sodium hydroxide.
The suitable acid solution used in step (c) is selected from a solution of acid and water.
In general, The suitable acid is selected from sulfuric acid, hydrochloric acid and nitric acid. Most preferred acid is hydrochloric acid.
In one embodiment, the crystalline form C of the compound of Formula (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2?±0.2° at 8.1, 8.9, 10.2, 11.1 and 26.9.
In another embodiment, there is provided a crystalline form C of compound of Formula (I) characterized by X-ray powder diffraction pattern having peaks expressed in degrees 2?±0.2° at 5.7, 8.1, 8.9, 10.2, 10.7, 11.1, 11.4, 14.6, 16.2, 18.9, 19.6, 21.2, 21.6, 22.5, 22.7, 25.6°, 26.6, 26.9 and 28.1.
In another embodiment there is provided Form D of compound of formula (I), which can be further characterized by its powder X-ray diffraction pattern (PXRD) as depicted in Fig. 4.
In another embodiment there is provided a process for the preparation of Form D which comprises,
a) dissolving compound of Formula (I) in a suitable solvent at suitable temperature;
b) cooling the reaction mixture at suitable temperature and stirring the reaction mixture for suitable time to precipitate out solid;
a) isolating the resulting precipitated solid as crystalline Form D.
The suitable solvent used in step (a) is selected from the group comprising tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, di-tert-butyl ether, dipropylene glycol methyl ether, dibutyl ether, diethyl ether, diisopropyl ether, dimethoxyethane, dimethoxymethane, 1,4-dioxane , ethyl tert-butyl ether, methyl tert-butyl ether or mixtures thereof. Most preferred solvent is tetrahydrofuran.
Suitable temperature for dissolving the compound is 60 °C to 90 °C, preferably 70 °C to 80 °C.
In one embodiment, the crystalline form D of the compound of Formula (I) is characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2?±0.2° at 11.1°.
In another embodiment, there is provided a crystalline form D of compound of Formula (I) characterized by X-ray powder diffraction pattern having peaks expressed in degrees 2?±0.2° at 10.1, 11.1, 14.6, 18.8, 22.4 and 26.8.
It will be appreciated that a skilled person may modify/alter these processes suitably in an obvious manner and such obvious alternations/modifications are considered included within the scope of the present application.
In another general aspect, there is provided a pharmaceutical composition comprising crystalline forms of compound of Formula (I) and pharmaceutically acceptable excipients. Excipients are added to the composition for a variety of purposes. Excipients are added to the composition for preparing various dosage forms using the techniques and processes known. Further, the pharmaceutical composition of the present invention may also comprise second active pharmaceutical substance other than the compound of formula (I).
Pharmaceutically acceptable excipients that may be used in the pharmaceutical compositions of this invention include, but are not limited to, microcrystalline cellulose, starch, croscarmellose sodium, lactose monohydrate, hypromellose, polyvinyl pyrrolidone, colloidal silicon dioxide, talc and magnesium stearate or mixtures thereof..
In another general aspect, there is provided a pharmaceutical composition comprising
crystalline Form A, crystalline Form B, crystalline Form C and crystalline Form D of compound of Formula (I) useful in the treatment of conditions associated with anemia.
Analytical methods:
XRD: The complete X-ray powder spectrum was recorded using a BP/AR/XRPD-02/345 X-Ray Powder Diffractometer model using Copper radiation. Step Size0.030 °, TPS76.80 s, Divergent Slit0.300 °, Antiscatter Slit3.000 mm, DetectorLYNXEYE (1D mode)Cu40.0 kV40.0 mA.
The process described in the present invention is exemplified further in the following examples which are provided for illustration only and should not be construed to limit the scope of the invention in any way.
Example – 1: Preparation of crystalline form A of compound of Formula (I)
In a 1000 mL round bottom flask, compound of Formula (I) (5 g) was added in acetone (500 mL) at 25-35 °C and dissolved it. Lyophilized it at -75 oC + 5oC to obtain 4 g (80%) of crystalline compound having purity > 99.80%. The X-ray powder diffraction pattern is depicted in Figure 1.
Example – 2: Preparation of crystalline form B of compound of Formula (I)
In a 500 mL round bottom flask, compound of Formula (I) (5 g) was added in tetrahydrofuran (250 mL) at 25-35 °C and dissolved it. After spray drying it to obtain 1.5 g (30%) of crystalline compound having purity > 99.50%. The X-ray powder diffraction pattern is depicted in Figure 2.
Example – 3: Preparation of crystalline form C of compound of Formula (I)
A mixture of Glycine coupled product (20g), Methanol (140 mL) and water (80 mL) was stirred for 5-10 minutes at 25-35 oC. Sodium hydroxide solution (60 mL, 2.3 M) was added in 10 min at 25-35 oC. Reaction mass was stirred for 30 minutes at 25-35 oC. Filtered reaction mixture to get clear solution. Diluted with water (560 mL) at 25-35 oC. Hydrochloric acid solution (~15%, 40 mL) was added slowly dropwise in 1 hr. at 25-35 oC. Stirred it for 1 hour at 25-35 oC. Solid was filtered and washed with water (4 x 100 mL) and dried at 70-75 oC to obtain 16 g (87%) of crystalline compound having purity > 99.70%. The X-ray powder diffraction pattern is depicted in Figure 3.

Example – 4: Preparation of crystalline form D of compound of Formula (I)
In a 250 mL round bottom flask, compound of Formula (I) (5 g) was added in 2-Methyl THF (100 mL) at 25-35 °C. The temperature of the reaction mixture was raised to 75-80 °C to dissolve solid. The reaction mass was cooled to 25-30 °C. The reaction mass was then filtered under suction. Wet cake was then dried at 70-75 °C for 3-4 hours to obtain 3.7 g (74%) crystalline compound having purity > 99.80%. The X-ray powder diffraction pattern is depicted in Figure 4.


,CLAIMS:We claim:
1. Crystalline forms of compound of Formula (I)

Formula I

wherein the crystalline forms is crystalline Form A, crystalline Form B, crystalline
Form C and crystalline Form D .
2. The crystalline Form A as claimed in claim 1 having a powder X-ray diffraction pattern as shown in FIG. 1 having at least three of characteristic powder X-ray diffraction pattern peaks expressed at about 10.2, 11.1 and 26.8 ±0.2 degree 2 theta.
3. The crystalline Form A as claimed in claim 1 having characteristic powder X-ray diffraction pattern peaks expressed at about 9.4, 10.2, 11.1, 14.5, 18.2, 18.8, 21.0, 21.5, 22.7 and 28.1 ±0.2 degree 2 theta.
4. The process for the preparation of crystalline form A as claimed in claim 1 comprising,
a) dissolving compound of formula (I) in a suitable solvent selected from acetone under suitable condition;
b) Isolating the resulting solid as crystalline Form A.
5. The crystalline Form B as claimed in claim 1 having a powder X-ray diffraction pattern as shown in FIG. 2 having at least three of characteristic powder X-ray diffraction pattern peaks expressed at about 8.0, 8.9 and 25.6 ±0.2 degree 2 theta.
6. The crystalline Form B as claimed in claim 1 having characteristic powder X-ray diffraction pattern peaks expressed at 5.7, 8.0, 8.9, 10.1, 10.7, 11.4, 16.2, 19.2, 21.4, 22.0, 22.7, 25.6, 26.6, 26.8 and 29.6 ±0.2 degree 2 theta.
7. The process for the preparation of crystalline form B as claimed in claim 1 comprising,
a) dissolving compound of formula (I) in a suitable solvent selected from tetrahydrofuran under suitable condition;
b) isolating the resulting solid as crystalline Form B.
8. The crystalline Form C as claimed in claim 1 having a powder X-ray diffraction pattern as shown in FIG. 3 having at least three of characteristic powder X-ray diffraction pattern peaks expressed at about 8.1, 8.9, 10.2, 11.1 and 26.9 ±0.2 degree 2 theta.
9. The crystalline Form C as claimed in claim 1 having characteristic powder X-ray diffraction pattern peaks expressed at about 5.7, 8.1, 8.9, 10.2, 10.7, 11.1, 11.4, 14.6, 16.2, 18.9, 19.6, 21.2, 21.6, 22.5, 22.7, 25.6, 26.6, 26.9 and 28.1 ±0.2 degree 2 theta.
10. The process for the preparation of crystalline form C as claimed in claim 1 comprising,
a) dissolving compound of Formula (I) in a suitable solvent mixture selected from alcohol and water to obtain a first reaction mixture;
b) adding suitable base selected from sodium hydroxide to the mixture obtained from step (a);
c) adding suitable acid solution selected from hydrochloric acid and water to the mixture obtained from step (b);
d) isolating the resulting precipitated solid as crystalline Form C.
11. The crystalline Form D as claimed in claim 1 having a powder X-ray diffraction pattern as shown in FIG. 4 having characteristic powder X-ray diffraction pattern peaks expressed at about 11.1 ±0.2 degree 2 theta.
12. The crystalline Form D as claimed in claim 1 having characteristic powder X-ray diffraction pattern peaks expressed at about 10.1°, 11.1°, 14.6°, 18.8°, 22.4 and 26.8°±0.2 degree 2 theta.
13. The process for the preparation of Form D as claimed in claim 1 comprising,
a) dissolving compound of Formula (I) in a suitable solvent selected from tetrahydrofuran at suitable temperature;
b) cooling the reaction mixture at suitable temperature selected from 60º C to 90ºC preferably from 70º C to 80ºC and stirring the reaction mixture for suitable time to precipitate out solid;
c) isolating the resulting precipitated solid as crystalline Form D.
14. A pharmaceutical composition comprising crystalline Form A, crystalline Form B, crystalline Form C and crystalline Form D of compound of Formula (I) as claimed in claim 1 useful in the treatment of conditions associated with anemia.
Dated this the 15th day of July 2022.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
of SUBRAMANIAM & ASSOCIATES
Attorneys for the applicants