DESC:PROCESS FOR PREPARATION OF SOLID DISPERSIONS OF MAVACAMTEN

FIELD OF THE INVENTION
The present application relates to process for preparation of amorphous form of Mavacamten, amorphous solid dispersions of Mavacamten, and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Mavacamten, has a chemical name 6-(((1S)-1-Phenylethyl)amino)-3-propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione, and is represented by the structure of formula I.

MyoKardia is developing Mavacamten, an allosteric modulator of cardiac myosin that targets aberrant sarcomeres, for the potential oral treatment of genetic cardiomyopathies including obstructive hypertrophic cardiomyopathy (HCM) and-obstructive HCM.

Mavacamten, its synthetic process and its pharmaceutical compositions are described in US patent No. 9,181,200 and US patent No. 9,585,883.

PCT publication WO 2021/092598 A1 describes crystalline Form A of Mavacamten and process thereof.

PCT publication WO 2021/154904 A1 describes crystalline Form 1, 2, 4, 5 and Form 6, their preparative methods and pharmaceutical compositions thereof.
PCT publication WO2022/162701A1 describes amorphous solid dispersions, process for preparation of amorphous form and crystalline Form A, B, C, D, and Form E and pharmaceutical compositions thereof.

Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Discovering new polymorphic forms, solvates and salts of a pharmaceutical product can provide 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 polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof 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., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Mavacamten. There is a clear need to develop a robust process to produce stable and pure solid-state forms of Mavacamten.

SUMMARY OF THE INVENTION

In one aspect the present application provides acid addition salts of Mavacamten and crystalline polymorphic forms thereof.

In a first aspect the present application provides process for preparation of solid dispersion of Mavacamten, the process comprising preparing acid addition salts of Mavacamten and converting the acid addition salts of Mavacamten into solid dispersions.

In another aspect the present application provides process for preparation of solid dispersion of Mavacamten, comprising:
a) providing an acid addition salt of Mavacamten and a solvent,
b) neutralizing the acid addition salt of Mavacamten with a suitable base,
c) adding a pharmaceutically acceptable excipient to the solution obtained in step (b),
d) removing the solvent from the solution obtained in step (c), and
e) isolating solid dispersion of Mavacamten.

In another aspect the present application provides process for preparation of an acid addition salt of Mavacamten, comprising:
a) reacting 6-chloro-3-isopropyl pyrimidine-2,4-dione or a salt thereof with (S)- (-)-a-methyl benzylamine or a salt thereof to form crude Mavacamten,
b) adding a suitable acid into the reaction mixture, and
c) isolating acid addition salt of Mavacamten.

In another aspect the present application provides process for preparation of an acid addition salt of Mavacamten, comprising:
a) providing a mixture of Mavacamten and a solvent,
b) adding a suitable acid into the mixture, and
c) isolating acid addition salt of Mavacamten.
In another aspect the present application provides pharmaceutical compositions comprising solid dispersions of Mavacamten prepared by the process described in this application and one or more pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF DRAWINGS

Figure-1 is powder X-ray diffraction (PXRD) pattern of crystalline Form of Mavacamten HCl salt prepared according to example 1.

Figure-2 is powder X-ray diffraction (PXRD) pattern of crystalline Form of Mavacamten tartrate salt prepared according to example 1.

Figure-3 is powder X-ray diffraction (PXRD) pattern of crystalline Form of Mavacamten oxalate salt prepared according to example 1.

Figure-4 is powder X-ray diffraction (PXRD) pattern of crystalline Form of Mavacamten mandelic acid salt prepared according to example 1.

Figure-5 is powder X-ray diffraction (PXRD) pattern of crystalline Form of Mavacamten succinic acid salt prepared according to example 1.

Figure-6 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Mavacamten with Copovidone according to example 2.

Figure-7 is powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion of Mavacamten with Eudragit L100-55 prepared according to example 3.

DETAILED DESCRITPION OF THE INVENTION

In one aspect the present application provides a process for preparation of amorphous form of Mavacamten, amorphous solid dispersions of Mavacamten, and pharmaceutical compositions thereof. Further, the present application provides acid addition salts of Mavacamten and crystalline polymorphic forms thereof.
In a first aspect the present application provides process for preparation of solid dispersion of Mavacamten, the process comprising preparing acid addition salts of Mavacamten and converting the acid addition salts of Mavacamten into solid dispersions.

In a specific aspect the present application provides process for preparation of solid dispersion of Mavacamten, comprising:
a) providing an acid addition salt of Mavacamten and a solvent,
b) neutralizing the acid addition salt of Mavacamten with a suitable base,
c) adding a pharmaceutically acceptable excipient to the solution obtained in step (b),
d) removing the solvent from the solution obtained in step (c), and
e) isolating solid dispersion of Mavacamten.

The acid addition salt of Mavacamten is selected from HCl, HBr, acetic acid, trifluoro acetic acid, phosphoric acid, sulfuric acid, oxalic acid, tartaric acid, mandelic acid or succinic acid.

The process involves mixing of acid addition salt of Mavacamten with a suitable solvent such as acetone, 1,4-dioxane, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane or THF; preferably, methanol, ethanol, ethyl acetate, and the resulted mixture is added with a suitable base such as sodium hydroxide, Lithium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate; preferably sodium carbonate, or potassium carbonate. The resulted mixture may be extracted with a suitable solvent and the solution may be filtered to get particle free solution. A pharmaceutically acceptable excipient is added to the solution and stirred for about 30 minutes to about 5 hours.

Suitable pharmaceutically acceptable excipients which may be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

In a preferred embodiment, the pharmaceutically acceptable excipients are PVP-K30, PVP-K90, Copovidone and Eudragit.

Solvent is removed from the solution. Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying, filtration or any other technique known in the art; preferably the solvent is removed by filtration.

Isolation of amorphous solid dispersion comprising Mavacamten and one or more pharmaceutically acceptable excipient can be achieved by using the processes known in the art.

The solid dispersion obtained may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Mavacamten is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising Mavacamten, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore, these ingredients may be combined during the preparation of solid dispersion or after the preparation of solid dispersion to control hygroscopicity and to improve stability.

In another aspect, the present application provides a pharmaceutical composition comprising Mavacamten solid dispersion of the present invention and a pharmaceutically acceptable carrier.

In another aspect the present application provides process for preparation of an acid addition salt of Mavacamten, comprising:
a) reacting 6-chloro-3-isopropyl pyrimidine-2,4-dione or a salt thereof with (S)- (-)-a-methyl benzylamine or a salt thereof to form crude Mavacamten,
b) adding a suitable acid into the reaction mixture, and
c) isolating acid addition salt of Mavacamten.

The process involves reaction of 6-chloro-3-isopropyl pyrimidine-2,4-dione or a salt thereof with (S)-(-)-a-methyl benzylamine or a salt thereof in presence of a suitable solvent such as Dioxane, THF, Methyl-THF, ether and the like. The compound of formula II can be prepared by the processes described in the art.

The compound, 6-chloro-3-isopropyl pyrimidine-2,4-dione, or a salt thereof, the solvent and the compound, (S)-(-)-a-methyl benzylamine, or a salt thereof are mixed and the resulted mixture may be stirred for about 2 hours to about 20 hours at a temperature of about 50 °C to about 100 °C.

After completion of the reaction the reaction mixture may be cooled to about 50 °C and a suitable solvent such as acetone, methanol, ethanol, isopropanol, ethyl acetate or THF may be added. A suitable acid such as HCl, HBr, acetic acid, trifluoro acetic acid, phosphoric acid, sulfuric acid, oxalic acid, tartaric acid, mandelic acid or succinic acid is added to the reaction mixture and stirred for 30 minutes to about 5 hours. The acid addition salt of mavacamten can be isolated by filtration.

In another aspect the present application provides process for preparation of an acid addition salt of Mavacamten, comprising:
d) providing a mixture of Mavacamten and a solvent,
e) adding a suitable acid into the mixture, and
f) isolating acid addition salt of Mavacamten.

The process involves adding a suitable solvent such as acetone, methanol, ethanol, isopropanol, ethyl acetate or THF; preferably acetone, to mavacamten to provide a mixture and adding a suitable acid such as HCl, HBr, acetic acid, trifluoro acetic acid, phosphoric acid, sulfuric acid, oxalic acid, tartaric acid, mandelic acid or succinic acid is added to the mixture.

The resulted mixture may be stirred for about 10 minutes to about 3 hours at about 10 °C to about 60 °C. The mixture may be cooled to about 30 °C and filtered to get the acid addition salt of Mavacamten.

The compound of this application can be characterized by X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray diffraction was measured using PANalytical X-ray diffractometer, Model: Empyrean. System description: CuK-Alpha 1 wavelength= 1.54060, voltage 45 kV, current 40 mA, divergence slit = 1/4°; Sample stage=Reflection-spinner. Revolution time [s]: 1.000; Scan type: Pre-set time; Detector – Pixcel; Measurement parameters: Start Position [°2Th.]: 3.0066; End Position [°2Th.]: 39.9916; Step Size [°2Th.]: 0.0130; Scan Step time [s]: 1.000.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise.

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.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

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. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES

Example-1: Preparation of Mavacamten acid addition salts

6-chloro-3-isopropyl pyrimidine-2,4-dione (100 g) and (S)-(-)-a-methyl benzylamine 192 g) were charged into a round bottom flask and the mixture was heated to 95 °C and maintained for 8 hours. Completion of the reaction was confirmed by TLC, and the reaction mass was cooled to 35 °C.
Acetone or a suitable solvent is added to the reaction mass, and a suitable acid was added and stirred the mixture to get mavacamten acid addition salt.

Crude Mavacamten Solvent Acid Product & Purity PXRD
10.4 g Acetone (50 mL) HCl
(dry HCl gas was passed at 35 °C) Mavacamten HCl salt 4.5 g
Purity: 99.8% Figure 1
10.4 g Acetone (50 mL) L-(+)-tartaric acid (3.84 g) in methanol (20 mL) Mavacamten tartrate salt 4.4 g
Purity: 97.64% Figure 2
10.4 g Acetone (50 mL) + methanol (20 mL) Oxalic acid dihydrate (4.3 g) in acetone (10 mL) Mavacamten oxalate salt 5.2 g
Purity: 98.96% Figure 3
12.27 g Acetone (50 mL) Mandelic acid (4.3 g) in acetone (10 mL) Mavacamten mandelic acid salt 8.0 g
Purity: 98.12% Figure 4
14.3 g Acetone (50 mL) Succinic acid (4.3 g) in acetone (10 mL) and methanol (10 mL) Mavacamten succinic acid salt 1.3 g
Purity: 99.46% Figure 5
10.4 g Acetone (50 mL) HCl
(dry HCl gas was passed at 5 °C) Mavacamten HCl salt 4.23 g
Purity: 99.8% Figure 1

Example-2: Preparation of Mavacamten Solid Dispersion with Copovidone

Mavacamten HCl salt (90 g) and a mixture of dichloromethane and methanol (80:20, 900 mL) were charged into a round bottom flask and stirred for 10 minutes. pH of the reaction mass was adjusted 8.1 with aqueous sodium carbonate solution and stirred for 10 minutes. Layers separated and the organic layer was washed with aqueous methanol (1×270 mL). Copovidone (75 g) and a mixture of dichloromethane and methanol (80:20, 3600 mL) were charged into a round bottom flask and stirred for 10 minutes. This clear solution was added to the organic layer containing mavacamten base and stirred for 30 minutes. The clear solution obtained was filtered through a micron filter and the filtrate was spray dried at 70 °C in presence of Nitrogen gas. The solid was dried under vacuum at 60 °C to get 152 g of amorphous mavacamten solid dispersion with copovidone. Purity: 99.9%; PXRD: Figure 6.

Example-3: Preparation of Mavacamten Solid Dispersion with Eudragit

Mavacamten HCl salt (90 g) and a mixture of dichloromethane and methanol (80:20, 900 mL) were charged into a round bottom flask and stirred for 10 minutes. pH of the reaction mass was adjusted 8.1 with aqueous sodium carbonate solution and stirred for 10 minutes. Layers separated and the organic layer was washed with aqueous methanol (1×270 mL). Eudragit L100-55 (75 g) and a mixture of dichloromethane and methanol (80:20, 3600 mL) were charged into a round bottom flask and stirred for 10 minutes. This clear solution was added to the organic layer containing mavacamten base and stirred for 30 minutes. The clear solution obtained was filtered through a micron filter and the filtrate was spray dried at 70 °C in presence of Nitrogen gas. The solid was dried under vacuum at 60 °C to get 150 g of amorphous mavacamten solid dispersion with Eudragit. Purity: 99.9%; PXRD: Figure 7. ,CLAIMS:We claim:

1. A process for preparation of solid dispersion of Mavacamten, comprising:
a) providing an acid addition salt of Mavacamten and a solvent,
b) neutralizing the acid addition salt of Mavacamten with a suitable base,
c) adding a pharmaceutically acceptable excipient to the solution obtained in step (b),
d) removing the solvent from the solution obtained in step (c), and
e) isolating solid dispersion of Mavacamten.

2. The process as claimed in claim 1, wherein in the step a) acid addition salt is selected from HCl, HBr, acetic acid, trifluoro acetic acid, phosphoric acid, sulfuric acid, oxalic acid, tartaric acid, mandelic acid and succinic acid.

3. The process as claimed in claim 1, wherein in the step a) solvent is selected from acetone, 1,4-dioxane, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane and THF.

4. The process as claimed in claim 1, wherein in the step b) suitable base is selected from sodium hydroxide, Lithium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

5. The process as claimed in claim 1, wherein in the step c) pharmaceutically acceptable excipient is selected from PVP-K30, PVP-K90, Copovidone and Eudragit.

6. A process for preparation of an acid addition salt of Mavacamten, comprising:
a) providing a mixture of Mavacamten and a solvent,
b) adding a suitable acid into the mixture, and
c) isolating acid addition salt of Mavacamten.

7. The process as claimed in claim 6, wherein in the step a) solvent is selected from acetone, methanol, ethanol, isopropanol, ethyl acetate and THF.

8. The process as claimed in claim 6, wherein in the step b) suitable acid is selected from HCl, HBr, acetic acid, trifluoro acetic acid, phosphoric acid, sulfuric acid, oxalic acid, tartaric acid, mandelic acid and succinic acid.

9. Use of the acid addition salt of Mavacamten prepared according to claim 6-8 for the preparation of solid dispersion of Mavacamten.