DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:
INTRODUCTION
Aspects of the present application provide process for preparation of amorphous of zuranolone, amorphous solid dispersion of zuranolone and polymer matrix is selected from eudragit L-100-55, HPMC AS, copovidone, Eudragit EPO or mixture thereof and crystalline form D1 of Zuranolone.
Zuranolone having a chemical name; 1-[2-[(3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyl-2,4,5,6,7,8,9,10, 11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl]pyrazole-4-carbonitrile is represented with structure as follows:

Formula I
Zuranolone is developed for the treatment of postpartum depression (PPD) in adults. Zuranolone is described in U.S. Pat. No. 9,512,165. Solid state forms of zuranolone are described in PCT Publication No. WO 2018/039378A1.
Different crystalline forms and amorphous solid dispersion of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability.
Discovering new crystalline form and amorphous solid dispersion of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New crystalline forms and amorphous solid dispersion of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, such as a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). Additional crystalline form and amorphous solid dispersion of Zuranolone remain desirable.
SUMMARY
In an aspect, the present application provides a process for the preparation of amorphous zuranolone, comprising the steps of:
a) dissolving zuranolone in a solvent; and
b) isolating amorphous form of Zuranolone.
In specific aspect, the present application provides a process for the preparation of amorphous zuranolone, comprising the steps of:
a) dissolving zuranolone in a solvent selected from formic acid, water, methanol, acetone and mixture thereof; and
b) isolating amorphous form of Zuranolone by spray drying or filtration.
In an aspect, the present application provides amorphous solid dispersion of zuranolone and polymer matrix is selected from eudragit L-100-55, HPMC AS, copovidone, Eudragit EPO or mixture thereof.
In an aspect, the present application provides a process for the preparation of amorphous solid dispersion of zuranolone, and polymer matrix is selected from eudragit L-100-55, HPMC AS, copovidone, Eudragit EPO or mixture thereof, comprising the steps of:
a) contacting zuranolone with polymer matrix is selected from eudragit L-100-55, HPMC AS, copovidone, Eudragit EPO or mixture thereof in solvent; and
b) isolating the amorphous solid dispersion of Zuranolone.
In another aspect, the present application provides crystalline form D1 of zuranolone characterized by an XRPD pattern having peaks at 5.8°, 10.6°, 14.9° and 19.7°±0.2° 2?.
In another aspect, the present application provides process for the preparation of crystalline form D1 of zuranolone, comprising the steps of:
a) dissolving zuranolone in a solvent; and
b) isolating the crystalline form D1 of zuranolone.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous form of zuranolone prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous form of zuranolone prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and eudragit L-100-55 prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and HPMC AS prepared by the method of Example No 4.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and copovidone prepared by the method of Example No 5.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and eudragit EPO prepared by the method of Example No 6.
Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline form D1 of zuranolone prepared by the method of Example No 7.

DETAILED DESCRIPTION
In an aspect, the present application provides a process for the preparation of amorphous zuranolone, comprising the steps of:
a) dissolving zuranolone in a solvent; and
b) isolating amorphous form of Zuranolone.
In embodiments, solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, formic acid, water or mixtures thereof.
In embodiments, a solution of zuranolone may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of zuranolone may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: filtration, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.
In specific aspect, the present application provides a process for the preparation of amorphous zuranolone, comprising the steps of:
a) dissolving zuranolone in a solvent selected from formic acid, water, methanol, acetone and mixture thereof; and
b) isolating amorphous form of Zuranolone by spray drying or filtration.
In embodiments, a solution of zuranolone may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of zuranolone may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
Figure1 is an illustrative X-ray powder diffraction pattern of amorphous form of zuranolone prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous form of zuranolone prepared by the method of Example No 2.
In an aspect, the present application provides amorphous solid dispersion of zuranolone comprising an amorphous zuranolone and polymer matrix selected from eudragit L-100-55, HPMC AS, copovidone, Eudragit EPO or mixture thereof .
In an aspect, the present application provides a process for the preparation of amorphous solid dispersion of zuranolone and polymer matrix is selected from eudragit L-100-55, HPMC AS, copovidone, Eudragit EPO or mixture thereof , comprising the steps of:
(a) contacting zuranolone with polymer matrix is selected from eudragit L-100-55, HPMC AS, copovidone, Eudragit EPO or mixture thereof in solvent; and
(b) isolating the amorphous solid dispersion of Zuranolone.
In embodiments, solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof.
In embodiments, a solution of zuranolone may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of zuranolone may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and eudragit L-100-55 prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and HPMC AS prepared by the method of Example No 4.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and copovidone prepared by the method of Example No 5.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of zuranolone and Eudragit EPO prepared by the method of Example No 6.
In another aspect, the present application provides crystalline form D1 of zuranolone characterized by an XRPD pattern having peaks at 5.8°, 10.6°, 14.9° and 19.7°±0.2° 2?.
In an embodiment, the application provides crystalline form D1 of zuranolone, characterized by a PXRD pattern having one or more additional peaks at about 9.0°, 11.4°, 15.6° and 21.4°±0.2° 2?.
In another aspect, the present application provides process for the preparation of crystalline form D1 of zuranolone, comprising the steps of:
a) dissolving zuranolone in a solvent; and
b) isolating the crystalline form D1 of zuranolone.
In embodiments, solvent may be selected from the group consisting of acetic acid, n-heptane, methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone; methyl acetate, ethyl acetate, isopropyl acetate, water or mixtures thereof.
In embodiments, a solution of zuranolone may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments, a solution of zuranolone may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: filtration, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.
Figure 7 is an illustrative X-ray powder diffraction pattern of crystalline form D1 of zuranolone prepared by the method of Example No 7.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline form D of zuranolone or amorphous zuranolone and atleast one additional pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like.
In another aspect, the present application provides crystalline form D of zuranolone or amorphous zuranolone, having chemical purity more than 99% by HPLC or more than 99.5% by HPLC or more than 99.9% by HPLC.
In another aspect, the present application provides zuranolone particle size (D90) of zuranolone may be less than 100 microns or less than 50 microns or less than 20 microns.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
Examples
Example 1: Process for the preparation of amorphous form of Zuranolone.
Zuranolone (200 mg) was dissolved in formic caid (2.5 mL) at 60°C. The obtained clear solution was filtered to make it particle free. Water 5 (mL) was added to the solution and stirred for 1 hour and 30 minutes at 30°C. The obtained solid was filtered and dried under vacuum to obtain the title compound.

Example 2: Process for the preparation of amorphous form of Zuranolone.
Zuranolone (4 g) was dissolved in a mixture of methanol (50 mL) and acetone (50 mL) at 50°C. The obtained clear solution was filtered to make it particle free. The particle free solution was spray dried to obtain the title compound.

Example 3: Process for the preparation of amorphous solid dispersion of Zuranolone and eudragit L-100-55.
Zuranolone (3 g) was dissolved in a mixture of methanol (50 mL) and acetone (50 mL) at 50°C. The obtained clear solution was filtered to make it particle free. Eudragit L-100-55 (3 g) was dissolved in methanol (50 mL) at 50°C. The obtained clear solution was mixed with Zuranolone solution and spray dried to obtain the title compound.

Example 4: Process for the preparation of amorphous solid dispersion of Zuranolone and HPMC AS.
Zuranolone (3 g) was dissolved in a mixture of methanol (50 mL) and acetone (50 mL) at 50°C. The obtained clear solution was filtered to make it particle free. HPMC AS (3 g) was dissolved in methanol (50 mL) at 50°C. The obtained clear solution was mixed with Zuranolone solution and spray dried to obtain the title compound.

Example 5: Process for the preparation of amorphous solid dispersion of Zuranolone and copovidone.
Zuranolone (3 g) was dissolved in a mixture of methanol (50 mL) and acetone (50 mL) at 50°C. The obtained clear solution was filtered to make it particle free. Copovidone (3 g) was dissolved in methanol (50 mL) at 50°C. The obtained clear solution was mixed with Zuranolone solution and spray dried to obtain the title compound.

Example 6: Process for the preparation of amorphous solid dispersion of Zuranolone and eudragit EPO.
Zuranolone (2 g) was dissolved in a mixture of methanol (50 mL) and acetone (50 mL) at 50°C. The obtained clear solution was filtered to make it particle free. Eudragit EPO (2 g) was dissolved in methanol (50 mL) at 50°C. The obtained clear solution was mixed with Zuranolone solution and spray dried to obtain the title compound.

Example 7: Process for the preparation of crystalline form D1 of Zuranolone.
Zuranolone (200 mg) was dissolved in acetic acid (2.5 mL) at 60°C. The obtained clear solution was filtered to make it particle free. n-Heptane (10 mL) was added to the solution and stirred for 1 hour. The obtained solid was filtered and dried under vacuum to obtain the title compound.

Dated: 6th of Jan 2025.

Signature: _________________
Dr. B.Dinesh kumar
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited.
,CLAIMS:We Claim:

1. A process for the preparation of amorphous zuranolone, comprising:
a) dissolving zuranolone in a solvent; and
b) isolating amorphous form of Zuranolone.

2. The process according to claim 1, wherein the solvent selected from formic acid, water, methanol, acetone or mixture thereof.

3. The process according to claim 1, wherein the amorphous form is in the form of amorphous slod dispersion comprising zuranolone and polymer matrix.

4. The process according to claim 3, wherein the polymer matrix is selected from eudragit L-100-55, HPMC AS, copovidone, eudragit EPO or mixture thereof.

5. Crystalline form D1 of zuranolone characterized by an XRPD pattern having peaks at 5.8°, 10.6°, 14.9° and 19.7°±0.2° 2?.

6. A process for the preparation of crystalline form D1 of zuranolone, comprising the steps of:
a) dissolving zuranolone in a solvent; and
b) isolating the crystalline form D1 of zuranolone.