DESC:
FIELD OF THE INVENTION:
The present invention relates to an amorphous form of Clascoterone.
The present invention also relates to a process for the preparation of an amorphous form of Clascoterone.
BACKGROUND OF THE INVENTION:
Clascoterone is chemically known as cortexolone 17a-propionate, having the structure of Formula-I,

[Formula-I]
Clascoterone has been developed by Sun Pharmaceutical Industries Ltd. Clascoterone was approved by USFDA on Aug 26, 2020, under the proprietary name WINLEVI ®. Clascoterone is an androgen receptor inhibitor indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.
U.S. patent number US3152154 first discloses Clascoterone.
U.S. patent number US8785427 discloses different polymorphs of Clascoterone namely Crystalline Form I, Form II, and Form III. This patent also discloses Crystalline form IV which is in solvate form and obtained through crystallisation from propylene glycol/water in a ratio of 1/1 or polyethylene glycol/water in a ratio of 1/1.
U.S. patent application number US20220324901 discloses hydrated crystalline form of Clascoterone.
Although Clascoterone exists in multiple solid forms; most of the solid forms of Clascoterone suffer from drawbacks such as poor stability, poor solubility, poor flowability, unsuitability for industrial production or risk of solid-state transformations during the manufacturing processes and storage. Therefore, it is necessary to conduct further screening of Clascoterone to find solid form which solves problem of prior art like stability, solubility, flowability and which is more suitable for drug development.
Discovering new solid-state forms 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 solid-state forms 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, e.g., 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). For at least these reasons, there is a need for additional solid-state forms of Clascoterone.
The inventors of the present invention have developed amorphous form of Clascoterone which solves problems of prior art like poor stability, poor solubility, poor flowability, unsuitability for industrial production etc. and has also provided commercially viable process to produce an amorphous form. Process is simple, efficient, economical, less time consuming and industrially advantageous on a large scale.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide amorphous form of Clascoterone of Formula-I.
Another object of the present invention is to provide an industrially advantageous process for the preparation of amorphous form of Clascoterone of Formula-I.

SUMMARY OF INVENTION:
First aspect of the present invention is to provide an amorphous form of Clascoterone of Formula-I,

[Formula-I].
Second aspect of the present invention is to provide a process for the preparation of amorphous form of Clascoterone of Formula-I,

[Formula-I]
comprising the steps of:
a) treating Clascoterone with solvent; and
b) isolating amorphous form of Clascoterone of Formula-I.
Third aspect of the present invention is to provide a pharmaceutical composition comprising amorphous form of Clascoterone of Formula-I,

[Formula-I]
and a pharmaceutically acceptable excipient or carrier.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: X-ray powder diffractogram (XRPD) of amorphous form of Clascoterone of Formula-I obtained according to Example 01.
DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
According to first embodiment, the present invention provides amorphous form of Clascoterone of Formula-I,

[Formula-I].
In the first embodiment, amorphous form of Clascoterone of Formula-I can be characterized by X-ray powder diffractogram (XRPD) as shown in Figure 1.
According to second embodiment, the present invention provides a process for the preparation of amorphous form of Clascoterone of Formula-I,

[Formula-I]
comprising the steps of:
a) treating Clascoterone with solvent; and
b) isolating amorphous form of Clascoterone of Formula-I.
In the second embodiment, Clascoterone used as a starting material can be prepared by process known in the prior art.
In the second embodiment, treatment of Clascoterone with solvent in step a) can be carried out by dissolving or slurring Clascoterone in solvent.
In the second embodiment, dissolution of Clascoterone in solvent can be carried out at room temperature or by heating to an ambient temperature such as up to reflux temperature of solvent to obtain solution of Clascoterone.
In the second embodiment, mixture of Clascoterone and solvent can be stirred at a room temperature or at ambient temperature such as at reflux temperature of solvent until it dissolves completely.
In the second embodiment, dissolution of Clascoterone in solvent can also be carried out under reduced pressure with or without stirring.
In the second embodiment, dissolution enhancers such as surfactants, polymers or hydrophilic binders can be added to increase dissolution of Clascoterone in solvent.
In the second embodiment, obtained solution of Clascoterone can be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution can be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.
In the second embodiment, slurring of Clascoterone in solvent can be carried out by stirring the mixture of Clascoterone and solvent at a room temperature or at ambient temperature such as at reflux temperature of solvent to obtain suspension of Clascoterone.
In the second embodiment, solvent used in step a) can be selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the second embodiment, volume of solvent used with respect to Clascoterone used as starting material can be 5.0 volume to 15.0 volume.
In the second embodiment, isolation of amorphous form of Clascoterone of Formula-I in step b) can be carried out by removing solvent from the solution of clascoterone using the methods known in the art. Processes for removal of solvent can be selected from distillation or solvent evaporation under atmospheric pressure or reduced pressure, spray drying, freeze drying, agitated thin film drying and the like.
In the second embodiment, isolation of amorphous form of Clascoterone of Formula-I in step b) can also be carried out by any other technique of isolation known in the prior art including but not limited to filtration, precipitation, crystallization, centrifugation, sedimentation etc.
In the second embodiment, filtration can be carried out under gravity or under vacuum to obtain amorphous form of Clascoterone of Formula-I.
In the second embodiment, precipitation or crystallization of amorphous form can be carried out by cooling, by addition of anti-solvent, by addition of seed crystals or using combination of these processes.
In the second embodiment, obtained amorphous form of Clascoterone of Formula-I can be further dried by any of the process known in the art. Drying may be carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.

According to third embodiment, the present invention provides a pharmaceutical composition comprising amorphous form of Clascoterone of Formula-I,

[Formula I]
and a pharmaceutically acceptable excipient or carrier.
In the third embodiment, pharmaceutical composition can be in solid, semisolid, or in liquid form including but not limited to tablet, capsule, powder, pellet, cream, gel, paste, ointment, solution, suspension, emulsion, lotion etc.
In the third embodiment, pharmaceutical composition can be in ready to use form or may be reconstituted before use.
In the third embodiment, pharmaceutical composition can be used topically, orally, or systemically and can be prepared as sustained, controlled, modified and immediate release dosage forms.
In the third embodiment, suitable excipients and the amounts to use can be radially determined by the standard procedures and reference works in the field, and can be selected from e.g., emulsifiers, thickeners, preservatives, humectants, antioxidants, buffering agents, flavours, colouring agents, complexing agents, binders, diluents, fillers, lubricants, wetting agents, disintegrates etc.
All XRPD data reported in present invention are obtained using a PANalytical X-ray Powder Diffractometer, with copper Ka radiation.

XRPD Conditions:
Instrument Name X-ray Powder Diffractometer
Make & model Malvern PANalytical and Empyrean
Source CuLFF (Long fine focus)
Wavelength 1.5406 A?
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES:
The following example is illustrative of some of the embodiments of the present, invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 01: Preparation of amorphous form of Clascoterone of Formula-I
Clascoterone (1 g) was dissolved in 10 mL of dichloromethane and solvent was evaporated at 40°C. The isolated solid material was dried under vacuum at 25°C to 30°C for 4 hours to get the titled amorphous form of Clascoterone of Formula-I (850 mg).

Dated this 21st day of June 2024

Mr. Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd. ,CLAIMS:
I / We Claim:
1. An amorphous form of Clascoterone of Formula-I,

[Formula-I].

2. A process for the preparation of amorphous form of Clascoterone of Formula-I,

[Formula-I].
comprising the steps of:
a) treating Clascoterone with solvent; and
b) isolating amorphous form of Clascoterone of Formula-I.

3. The process as claimed in claim 02, wherein solvent in step a) is selected from the group consisting of alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
4. The process as claimed in claim 02, wherein treatment of Clascoterone with solvent in step a) is carried out by dissolving or slurring Clascoterone in solvent.
5. A pharmaceutical composition comprising amorphous form of Clascoterone of Formula-I,

[Formula-I]
and a pharmaceutically acceptable excipient or carrier.

Dated this 21st day of June 2024

Mr. Raju Sharma,
Sr. Manager-IPR,