DESC:PROCESS FOR PREPARATION OF CRYSTALLINE FORM A OF MAVACAMTEN

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 WO 2021/092598 A1 describes crystalline Form A of Mavacamten and process thereof.
Teva’s international patent application publication WO 2021/154904 A1 describes crystalline Form 1, 2, 4, 5 and Form 6, 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 process for preparation of crystalline Form A of Mavacamten, characterized by a PXRD pattern comprising peaks at about 11.6, 15.7, 17.3, 18.7, 19.9, 22.3, 23.4, 25.6, 29.1 and 31.6 ± 0.2° 2?, comprising:
a) providing a solution of Mavacamten in acetic acid;
b) adding the solution of step (a) into water containing seed crystals of Form A; and
c) isolating crystalline Form A of Mavacamten.

In another aspect the present application provides pharmaceutical compositions comprising crystalline Form A 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 A of Mavacamten prepared according to example 1.

DETAILED DESCRITPION OF THE INVENTION
In one aspect the present application provides crystalline Form A of Mavacamten, characterized by a PXRD pattern comprising peaks at about 11.6, 15.7, 17.3, 18.7, 19.9, 22.3, 23.4, 25.6, 29.1 and 31.6 ± 0.2° 2?, comprising:
a) providing a solution of Mavacamten in acetic acid;
b) adding the solution of step (a) into water containing seed crystals of Form A; and
c) isolating crystalline Form A of Mavacamten.

The step (a) of the process involves mixing of Mavacamten with acetic acid. Acetic acid can be 1 v/w to 10 v/w to mavacamten. The mixture of mavacamten acetic acid may be hated to about 65 °C to get a clear solution. The solution obtained may be filtered through a celite bed or through a filter paper to get a particle free solution.

The step (b) involves addition of the solution of step (a) into water containing seed crystals of Form A. In a separate flask water is taken and seed crystals of Form A are added. Water can be 1 v/w to 10 v/w to mavacamten, and the seed crystals of Form A may about 0.01% wt/wt to about 10% wt/wt to the crude mavacamten. The solution of step (a) is added to water containing seed crystals of Form A over a period of about 10 minutes to about 3 hours. The resultant mixture may be stirred for about 30 minutes to about 10 hours at 20 °C to about 50 °C.

The step (c) involves isolation of crystalline Form A of Mavacamten. The crystalline Form A of Mavacamten is isolated from the suspension by filtration or by decantation or by any suitable method. The wet material may be washed with water. The crystalline Form A of Mavacamten may be dried under vacuum.

In another aspect, the crystalline Form A of Mavacamten is further characterized by a PXRD pattern comprising the peaks at about 10.1, 11.6, 13.7, 14.6, 15.7, 16.2, 17.3 18.7, 19.9, 21.3, 22.3, 23.4, 23.8, 24.1, 24.5, 24.8, 25.6, 26.1, 27.3, 27.7, 29.1, 29.9, 31.6, 32.4, 32.7, 34.7, 36.1, 37.8, 38.5 and 39.6 ± 0.2° 2?.

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

In another embodiment, the present application provides pharmaceutical compositions comprising crystalline Form A of Mavacamten 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

Example-1: Preparation of Mavacamten Form A
Mavacamten (5 g) and acetic acid (20 mL) and were charged into a round bottom flask and stirred for 10 minutes at 30 °C. The mixture was heated to 65 °C and stirred for 15 minutes. The clear solution was filtered through a 0.45-micron filter paper. In another flask water (50 mL) and seed crystals of Form A (250 mg) were added and stirred for 10 minutes. The acetic acid and mavacamten solution is slowly added to water containing seed crystals of Form A over a period of 1 hour. The resultant mixture was stirred for 90 minutes at 30 °C. The precipitated material was filtered and the solid was washed with water (10 mL) and suck dried. The wet material was dried under at 60 °C until constant weight. Purity by HPLC: 99.70%
PXRD pattern is shown in Figure 1. ,CLAIMS:We claim:

1. A process for preparation of crystalline Form A of Mavacamten characterized by a PXRD pattern comprising peaks at about 11.6, 15.7, 17.3, 18.7, 19.9, 22.3, 23.4, 25.6, 29.1 and 31.6 ± 0.2° 2?, the process comprising:
a) providing a solution comprising Mavacamten and acetic acid;
b) adding the solution of step (a) into water containing seed crystals of Form A; and
c) isolating crystalline Form A of Mavacamten.

2. Crystalline Form A of Mavacamten characterized by a PXRD pattern comprising peaks at about 11.6, 15.7, 17.3, 18.7, 19.9, 22.3, 23.4, 25.6, 29.1 and 31.6 ± 0.2° 2? prepared by the process comprising the steps of:
a) providing a solution comprising Mavacamten and acetic acid;
b) adding the solution of step (a) into water containing seed crystals of Form A; and
c) isolating crystalline Form A of Mavacamten.

3. A pharmaceutical composition comprising crystalline Form A of Mavacamten prepared by the process claimed in claim 1 and one or more pharmaceutically acceptable excipients.