DESC:FIELD OF THE INVENTION

The present application relates to process for preparation of crystalline polymorphic forms 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.

MyoKardia’s international patent application publication WO2021/092598A1 describes crystalline Form A of Mavacamten and process thereof.

Teva’s international patent application publication WO2021/154904A1 describes crystalline Form 1, 2, 4, 5 and Form 6, their preparative methods and pharmaceutical compositions thereof.

International patent application publication WO2022/162701A1 describes crystalline Form A, B, C, D and Form E, their preparative methods 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 crystalline Forms of Mavacamten.
SUMMARY OF THE INVENTION

In one aspect the present application provides a Hot-Melt Extrusion process for preparation of crystalline Form D of Mavacamten characterized by a PXRD pattern comprising peaks at about 11.06, 14.4, 15.5, 16.9 and 19.1 ± 0.2° 2?.

In another aspect the present application provides pharmaceutical compositions comprising crystalline Form D of Mavacamten prepared by Hot-Melt Extrusion 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 D of Mavacamten prepared according to example 1.

DETAILED DESCRITPION OF THE INVENTION

The present application provides a Hot-Melt Extrusion process for preparation of stable crystalline Form D of Mavacamten.

In one aspect the present application provides a Hot-Melt Extrusion process for preparation of stable crystalline Form D of Mavacamten characterized by a PXRD pattern comprising peaks at about 11.06, 14.4, 15.5, 16.9 and 19.1 ± 0.2° 2?.

The process involves adding mavacamten to a hot melt extruder preheated to 120°C, set the screw speed to 100 rpm, and cool and crush the extrudable to obtain stable Form D.

In one aspect the present application provides a Hot-Melt Extrusion process for preparation of stable crystalline Form D of Mavacamten, the process involves mixing mavacamten with a suitable polymer, adding the mixture to a hot melt extruder preheated to 120 °C, set the screw speed to 100 rpm, and cool and crush the extrudable to obtain stable Form D.

In another aspect, the crystalline Form D of Mavacamten is characterized by the PXRD pattern of Figure 1.

In another embodiment, the present application provides pharmaceutical compositions comprising crystalline Form D of Mavacamten prepared by Hot-Melt Extrusion process described in this application and one or more pharmaceutically acceptable excipient.

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

Hot-melt extrusion was performed with a HAAKE™ MiniCTW Micro-Conical Twin Screw hot-melt extruder from Thermo Fischer Scientific Inc.
Examples 1-6
General procedure: Weighed and taken Mavacamten (Form A) or blended appropriate amounts of relevant polymer and Mavacamten (Form A). Pre-set the screw to desired temperature, mode to either extrusion or circulation and rpm (speed). Once temperature achieved added the material through feeder and collected the extruded material from extruder side. Characterized the obtained material.

Ingredients / Parameters Ex-1 Ex-2 Ex-3 Ex-4 Ex-5 Ex-6
Mavacamten (g) 3.2 2.25 3.2 3.6 3.6 2.7
Polymer (g) Copovidone 0.8 0.25 0.8 0.4 -- 0.3
Soluplus -- -- -- -- 0.4 --
API Polymer ratio 4:1 9:1 4:1 9:1 9:1 9:1
Feeding Temp. °C 220 220 220 220 220 230
Expt/Final Temp. °C 220 220 220 220 220 230
Recirculation / Extrusion Recln. and then extrn. Extrn. mode Extrn. mode Extrn. mode Extrn. mode Extrn. mode
Torque / Nm 0.04-0.15-0.55/ 0.55 0.07 to 0.5 0.21 to 0.15 0.09 to 1.09 to 0.39 0.34 to 1.54 to 0.49 0.73 to 0.13
RPM 20 20 60 30 60 60
PXRD of Material Initial Form D Form D Form D Form D Form D Form D
Middle Form D +
Form A Form D Form D Form D Form D Form D
Final Form D Form D Form D Form D Form D

PXRD of the final material obtained in example-2 is shown in Figure 1.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto. ,CLAIMS:1. A process for preparation of crystalline Form D of Mavacamten characterized by a PXRD pattern comprising peaks at about 11.06, 14.4, 15.5, 16.9 and 19.1 ± 0.2° 2? by Hot-Melt Extrusion.

2. A process for preparation of crystalline Form D of Mavacamten characterized by a PXRD pattern comprising peaks at about 11.06, 14.4, 15.5, 16.9 and 19.1 ± 0.2° 2? by Hot-Melt Extrusion; wherein the process involves adding mavacamten to a hot melt extruder preheated to 120°C, set the screw speed to 100 rpm, and cool and crush the extrudable to obtain Form D.

3. The process as claimed in claim 2, wherein in the process involves mixing mavacamten with a suitable polymer, adding the mixture to a hot melt extruder preheated to 120°C, set the screw speed to 100 rpm, and cool and crush the extrudable to obtain stable Form D.

4. The process as claimed in claim 3, wherein in the “suitable polymer” is selected from Copovidone or Soluplus.

5. A pharmaceutical composition comprising crystalline Form D of Mavacamten and one or more pharmaceutically acceptable excipient; wherein the crystalline Form D of Mavacamten is prepared by Hot-Melt Extrusion.