DESC:SOLID STATE FORMS OF MAVACAMTEN
FIELD OF THE INVENTION
The present application relates to solid state forms of Mavacamten, process for
the preparation and pharmaceutical compositions 5 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-
10 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) and15
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.
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
20 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"), Xray
powder diffraction (XRPD or powder XRD) pattern, infrared absorption
fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more
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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 5 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
10 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.
15 SUMMARY OF THE INVENTION
In one aspect the present application provides crystalline Form H of
Mavacamten, characterized by a PXRD pattern comprising peaks at about 7.48, 15.02,
and 27.57 ± 0.2° 2?.
In another aspect the present application provides form H of Mavacamten,
20 characterized by a PXRD pattern as represented by figure 1.
In another embodiment, the present application provides a process for
preparation of crystalline Form H of Mavacamten, comprising:
a) providing Mavacamten in one or more of suitable solvents;
b) adding hydrochloric acid to the mixture obtained in step (a);
25 c) isolating crystalline Form H of Mavacamten.
In another aspect the present application provides pharmaceutical compositions
comprising crystalline form H of Mavacamten described in this application and one or
more pharmaceutically acceptable excipient.
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BRIEF DESCRIPTION OF DRAWINGS
Figure-1 is powder X-ray diffraction (PXRD) pattern of crystalline Form H prepared
according to example 1.
DETAILED DESCRITPION 5 OF THE INVENTION
In one aspect the present application provides crystalline Form H of
Mavacamten, characterized by a PXRD pattern comprising peaks at about 7.48, 15.02,
and 27.57 ± 0.2° 2?.
In another aspect the present application provides form H of Mavacamten,
10 characterized by a PXRD pattern as represented by figure 1.
In another aspect, the present application provides a process for preparation of
crystalline Form H of Mavacamten, comprising:
a) providing Mavacamten in one or more of suitable solvents;
b) adding hydrochloric acid to the mixture obtained in step (a);
15 c) isolating crystalline Form H of Mavacamten.
The step (a) of the process involves mixing of Mavacamten in a suitable solvent
such as acetone dichloromethane, n-heptane or a mixture thereof.
The step (b) involves addition of addition of hydrochloric acid to the mixture
of step (a). The hydrochloric acid can be aqueous hydrochloric acid or hydrochloric
20 acid dissolved in any organic solvent. After adding hydrochloric acid, the resultant
mixture may be stirred for about 2 hours to about 10 hours at 20 °C to about 50 °C.
The step (c) involves isolation of crystalline Form H of Mavacamten. The
crystalline Form H of Mavacamten is isolated from the suspension by filtration or by
decantation or by any suitable method. The crystalline Form H of Mavacamten may be
25 dried under vacuum.
In another aspect, the crystalline Form H of Mavacamten is further
characterized by a PXRD pattern comprising the peaks at about 13.74 and 17.27 ± 0.2°
2?.
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In another aspect, the crystalline Form H of Mavacamten is characterized by
the PXRD pattern of Figure 1.
In another embodiment, the present application provides pharmaceutical
compositions comprising crystalline form H of Mavacamten described in this
application and one or more pharmaceutically acceptable 5 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,
10 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
15 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
20 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
25 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.
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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
5 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
10 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
15 within the scope of this invention.
EXAMPLES
Example-1: Preparation of Mavacamten Form H
Mavacamten Form A (1 g), acetone (10 mL) and were charged into a conical
flask, and stirred for 10 minutes at 25 °C. Aqueous hydrochloric acid (678 µL) was
20 added and the resultant solution was stirred for 20 hours at 25 °C. The suspension was
filtered and the solid obtained dried under vacuum.
PXRD pattern is shown in Figure 1.
Example-2: Preparation of Mavacamten Form H
25 Mavacamten Form A (1 g), dichloromethane (10 mL) and were charged into a
conical flask, and stirred for 10 minutes at 25 °C. Aqueous hydrochloric acid (678 µL)
was added and the resultant solution was stirred for 20 hours at 25 °C. The suspension
was filtered and the solid obtained dried under vacuum.
PXRD pattern is shown in Figure 1.
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Example-3: Preparation of Mavacamten Form H
Mavacamten Form A (1 g), n-heptane (10 mL) and were charged into a conical
flask, and stirred for 10 minutes at ,CLAIMS:1. Crystalline Form H of Mavacamten, characterized by a PXRD pattern comprising
peaks at about 7.48, 15.02, and 5 27.57 ± 0.2° 2?.
2. Crystalline Form H of Mavacamten, characterized by a PXRD pattern as represented
by figure 1.
3. A process for preparation of crystalline Form H of Mavacamten, comprising:
a) providing Mavacamten in one or more of suitable solvents;
10 b) adding hydrochloric acid to the mixture obtained in step (a);
c) isolating crystalline Form H of Mavacamten.
4. Pharmaceutical compositions comprising crystalline form H of Mavacamten and one
or more pharmaceutically acceptable excipient.
5. Use of Crystalline Form H of Mavacamten in the preparation of pharmaceutical
15 compositions comprising Mavacamten and one or more pharmaceutically acceptable
excipient.