DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

SOLID STATE FORM OF MAVACAMTEN

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a novel solid-state form of Mavacamten, processes for the preparation thereof and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION
Mavacamten is an oral cardiac myosin inhibitor investigated for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM), non-obstructive HCM and precision diastolic disease. The chemical name of Macacamten is 3-(1-Methylethyl)-6-[[(1S)-1-phenylethyl] amino]-2,4(1H,3H)-pyrimidinedione. Mavacamten can be represented by the chemical structure of Formula I:

Mavacamten and its preparation are disclosed in US patent No. 9,181,200. The US ‘200 discloses a process for the preparation of Mavacamten and its isolation as a white solid from ethyl acetate and hexane. The same process is disclosed in example 1 of US patent No. 9,585,883.

WO2021/092598 discloses a crystalline form A of Mavacamten and process thereof. The process for the preparation of Form A involves recrystallization of Mavacamten from ethanol or an ethanol/water mixture.

WO2021/154904 discloses crystalline form 1, form 2, form 4, form 5, form 6 and amorphous form of Mavacamten, and process for the preparation thereof.

CN112939876 discloses crystalline form 1 of Mavacamten and process thereof.
WO2022/162701 discloses crystalline form A, form B, form C, form D, form E and solid dispersion of Mavacamten.

WO2022/189599 discloses crystalline form I, form II, form III, form IV, form V and form VI. This patent also discloses solvate forms of Mavacamten such as pyridine hemi-solvate, ??? hemi-solvate and chloroform mono-solvate.

IN202241029652 discloses crystalline form H of Mavacamten and its process.

A novel polymorphic form of a pharmaceutical active substance can lead to improved bioavailability, stability, yield, selectivity of chemical reactions and flowability of the material. The new polymorphic form of a pharmaceutical substance can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. Hence, there is a need to develop a novel solid-state form of Mavacamten with improved physicochemical properties.

OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a novel solid-state form of Mavacamten and processes for preparing thereof and pharmaceutical composition thereof.

SUMMARY OF THE INVENTION
In an aspect of the present invention provides a solid-state form of Mavacamten characterized by a PXRD pattern comprising two or more peaks at about 6.6, 7.7, 13.7, 15.6, 20.3, 21.5 and 23.2 ± 0.2° 2?.

In another aspect of the present invention provides a process for the preparation of the solid-state form of Mavacamten comprising:
a) providing a solution of Mavacamten in a solvent;
b) adding a second solvent to the solution obtained in step (a);
c) stirring the solution obtained in step (c); and
d) isolating solid state form of Mavacamten.
The present invention encompasses use of the solid-state form of Mavacamten for the preparation of pharmaceutical compositions and its medicament, particularly, as cardiac myosin inhibitor.

BRIEF DESCRIPTION OF ABBREVIATIONS AND DEFININTIONS
NMP N-Methyl-2-pyrrolidone
PXRD Powder X-ray diffractogram
DSC Differential scanning calorimetry
TGA Thermogravimetric analysis
DVS Dynamic vapor sorption

BRIEF DESCRIPTION OF THE FIGURES
Figure 1: PXRD pattern of crystalline MAV-2 of Mavacamten according to the present invention.
Figure 2: DSC curve of crystalline MAV-2 of Mavacamten according to the present invention.
Figure 3: TGA curve of crystalline MAV-2 of Mavacamten according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates a novel solid-state form of Mavacamten and a process for preparation and pharmaceutical composition thereof. The solid-state form includes but is not limited to crystalline and amorphous.

The solid-state form of the present invention may be referred herein as crystalline MAV-2 of Mavacamten. Further, the MAV-2 may be referred to as polymorphically pure or substantially free of any other polymorphic forms.

In an aspect of the present invention provides a crystalline MAV-2 of Mavacamten characterized by a PXRD pattern comprising two or more peaks at about 6.6, 7.7, 13.7, 15.6, 20.3, 21.5 and 23.2 ± 0.2° 2?.

In an embodiment, the crystalline MAV-2 characterized by DSC thermogram comprising a endothermic peaks with a peak onset of approximately 82°C and a peak maximum of approximately 96°C; and endothermic peaks with a peak onset of approximately 227°C and a peak maximum of approximately 235°C.

In an embodiment, the crystalline MAV-2 may be further characterized by one or more of following parameters:
- a PXRD pattern as depicted n Figure 1;
- a DSC curve as depicted in Figure 2; and
- TGA as depicted in Figure 3.

In another aspect the present invention provides a process for the preparation of crystalline form MAV-2 of Mavacamten comprising:
a) providing a solution of Mavacamten in a solvent;
b) adding a second solvent to the solution obtained in step (a);
c) stirring the solution obtained in step (c); and
d) isolating crystalline form MAV-2 of Mavacamten.

The step (a) of the process involves providing a solution of Mavacamten by dissolving Mavacamten in a suitable solvent or the solution obtained from the previous processing step of Mavacamten.

Suitable solvent used for providing a solution includes but are not limited to: alcohols, such as methanol, ethanol, 2-Propanol, n-butanol, isoamyl alcohol, ethylene glycol, 2-methoxy ethanol and 2-ethoxy ethanol; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; aliphatic hydrocarbons like n-hexane, cyclohexane, n-heptane and iso-octane and like; aromatic hydrocarbons like toluene and xylene; halogenated hydrocarbons, such as dichloromethane, dichloroethane and chloroform; nitriles, such as acetonitrile; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone and dimethyl sulfoxide; water; and any mixtures of two or more thereof.

The solution can be prepared by heating the contents at a temperature of less than about 100°C or less than about 50°C or less than about 40°C or less than about 30°C or less than about 20°C or reflux temperature of the solvents used. Mavacamten used for preparing solution can be in crystalline form or amorphous form or semi-solid or oily liquid. The obtained solution optionally filtered to remove undissolved particles, if any, suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The mavacamten starting material can be obtained by the procedure disclosed in example 1 of US patent No. 9,181,200.

The step (b) involves addition of a second solvent or mixtures thereof at a temperature of less than about 100°C or less than about 50°C or less than about 40°C or less than about 30°C or less than about 20°C.

Suitable second solvent different from first solvent and it may form single phase solvent system with first solvent. The first solvent and second solvent may be selected to make sure that the Mavacamten remains dissolved in the mixture. The second solvent that includes but are not limited to: ethers, such as diisopropyl ether, dimethoxy ethane, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; alcohols, such as alcohols, such as methanol, ethanol, 2-Propanol, n-butanol, isoamyl alcohol, ethylene glycol, 2-methoxy ethanol and 2-ethoxy ethanol and any mixtures of two or more thereof. The ratio of the solvent system in the range of 1:1 to 1:10.

The step (c) involves stirring of resultant mixture after adding the second solvent to precipitate or enhance the precipitation of the solid. The stirring step may be carried out over a period of about 60 hours or about 50 hours or about 40 hours or about 30 hours or about 10 minutes. The stirring step may be maintained at the same temperature, or the mixture may be subjected for heating and cooling. The temperature may range from 0°C to 100° or reflux temperature. The obtained solid is isolated from the suspension by filtration or by decantation or by any suitable method.

The step (d) involves drying of the solid obtained in step (c). The drying may be carried out using equipment such as a tray dryer, suck dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer and flash dryer, at atmospheric pressure or under reduced pressure. The drying may be carried out at a temperature less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperature, 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 period to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.

In another aspect, the crystalline form MAV-2 of Mavacamten is characterized by the PXRD pattern of Figure 1.

In an embodiment, the present invention provides a process for the preparation of crystalline MAV-2 of Mavacamten, which comprises dissolution of Mavacamten in ethylene glycol; addition of diglyme to the solution; and isolation of crystalline MAV-2 of Mavacamten.

In another embodiment, the present invention provides a crystalline MAV-2 of Mavacamten, which is stable and do not convert to other crystalline form under the stress conditions as stated below in Table 1:

Table 1
Crystalline form MAV-2 of Mavacamten
Stress conditions XRD result
Stored at 2-8°C 2 months Stable
Vacuum Tray dry at 100°C 30 mins Stable
Strong grinding Stable
80% RH 7days Stable
100% RH 7 days Stable

The crystalline MAV-2 of Mavacamten has good flow property at ISO angle 43°. This angle may be calculated from Angle of Repose instrument software.

The crystalline form MAV-2 of the present invention is non-hygroscopic based on DVS Isotherm analysis. Table 2 shows the non-hygroscopic nature of crystalline form MAV-2:

Table 2
Method: New DMDT method-0.001 DMDT-1Cycle
Temperature: 25.3°C
Target
% P/Po Change in Mass (%)- ref
Sorption Desorption Hysteresis
0.0 -0.0790 -0.0570
10.0 0.0059 -0.0519 -0.0578
20.0 0.0197 -0.0372 -0.0569
30.0 0.0323 -0.0192 -0.0515
40.0 0.0468 0.0030 -0.0437
50.0 0.0620 0.0306 -0.0314
60.0 0.0809 0.0690 -0.0119
70.0 0.0998 0.1013 0.0015
80.0 0.1128 0.1182 0.0054
90.0 0.1045 0.1045

The crystalline MAV-2 of Mavacamten can be characterized by Powder X-ray diffraction pattern, DSC and TGA determined in accordance with procedures that are known in the art. The PXRD peaks and pattern reported in the present invention, unless stated otherwise, are preferably measured on Bruker D8 advance with lynex detector equipped with Cu source (?=1.58Å). The DSC analysis is carried out using Mettler Toledo Q2000 instrument with scanning parameters of mass flow 50.0mL/min, equilibrate at 25.00°C and ramp 10.00°C/min to 300.00°C. The thermal analysis is carried out using Mettler Toledo TGA Q500 with ramp 10.00°C/min to 300.00°C.

The crystalline form MAV-2 of the present invention can be used for the preparation of amorphous form, solid dispersions, and pharmaceutical compositions with one or more pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipients which may be used 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 microcrystal line cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as HPMC -Phthalate, HPMC- AS, HPMC-15 CPS; pregelatinized starches and the like; disintegrant 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.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES

Example 1: Preparation of crystalline form MAV-2 of Mavacamten:
Mavacamten (0.1gm.) was dissolved in ethylene glycol (7 ml) at 85°C to obtain a clear solution and filtered for particle free clear solution. Diglyme (7 ml) was added to the above clear solution and stirred for 48 hours at 60°C. The solid obtained was filtered followed by suck dried for 30-40 minutes. The resultant solid was dried under vacuum for 10 hours at 70°C to obtain crystalline form MAV-2 of Mavacamten with yield of 0.045 gm.
The PXRD, DSC and TGA of the crystalline form MAV-2 are shown in Figure 1, Figure 2 and Figure 3.

The experiment was conducted for 10gm batch of Mavacamten in ethylene glycol (600 ml) and diglyme (600 ml) according to the above process and found reproducibility of crystalline MAV-2 of Mavacamten with yield of 4.5 gm.

Example 2: Preparation of crystalline form MAV-2 of Mavacamten:
Mavacamten (0.4gm) was dissolved in 2-methoxy ethanol and 2-ethoxy ethanol (1;1) (20ml) at 85°C to obtain a clear solution and filtered for particle free. 2-Propanol (20ml) was added slowly to above clear solution at 50°C and stirred for 24-48 hours at 50°C. The solid obtained was filtered followed by suck dried for 20-25 minutes to obtain crystalline form MAV-2 of Mavacamten with yield of 0.05gm. ,CLAIMS:WE CLAIM:

1. A crystalline form MAV-2 of Mavacamten, characterized by X-ray powder diffraction pattern comprising at least two or more peaks selected from 6.6, 7.7, 13.7, 15.6, 20.3, 21.5 and 23.2 ± 0.2° 2?.

2. The crystalline form MAV-2 as claimed in claim 1, characterized by a DSC thermogram comprising endothermic peaks with a peak onset of approximately 227°C and a peak maximum of approximately 235°C.

3. The crystalline form MAV-2 as claimed in claim 1, characterized by an X-ray powder diffraction pattern as depicted in figure 1, DSC curve as depicted in figure-2 and TGA as depicted in figure-3.

4. The crystalline form MAV-2 as claimed in claim 1, wherein pharmaceutical composition comprising a crystalline form MAV-2 of Mavacamten and one or more pharmaceutically acceptable excipients.

5. A process for preparation of crystalline form MAV-2 of Mavacamten characterized by a PXRD pattern comprising two or more peaks at about 6.6, 7.7, 13.7, 15.6, 20.3, 21.5 and 23.2 ± 0.2° 2? and the process comprising:
a) providing a solution of Mavacamten in a solvent;
b) adding a second solvent to the solution obtained in step (a);
c) stirring the solution obtained in step (c); and
d) isolating crystalline form MAV-2 of Mavacamten.

6. The process as claimed in claim 5, wherein the solvent of step (a) is selected from alcohols such as methanol, ethanol, 2-Propanol, n-butanol, isoamyl alcohol, ethylene glycol, 2-methoxy ethanol and 2-ethoxy ethanol or mixtures thereof.

7. The process as claimed in claim 5, wherein the second solvent is different from first solvent selected from alcohols such as methanol, ethanol, 2-Propanol, n-butanol, 2-methoxy ethanol, 2-ethoxy ethanol, ethylene glycol; ethers such as diisopropyl ether, dimethoxyethane, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl tetrahydrofuran, and diglyme or mixtures thereof.

8. The process as claimed in claim 5, wherein the first solvent of step (a) is selected from ethylene glycol, 2-methoxy ethanol, 2-ethoxy ethanol and second solvent of step (b) is selected from diglyme, 2-Propanol.

9. The process as claimed in claim 5, wherein the ratio of the solvent system is in the range of 1:1 to 1:10.

10. The process as claimed in claim 5, wherein the stirring is conducted for a period of 30 minutes to 50 hours.