DESC:
The following specification describes the nature of the invention:

CRYSTALLINE FORMS OF ENASIDENIB MESYLATE

FIELD OF THE INVENTION
The present application relates to solid state forms of Enasidenib mesylate and processes for preparation thereof.
The drug compound having the adopted name “Enasidenib mesylate”, chemically designated as 2-methyl-1-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)propan-2-ol methanesulfonate and is represented by structure of Formula I.

Formula I
Enasidenib is a mutated isocitrate dehydrogenase-2 (IDH-2m) inhibitor, developed for the potential oral treatment of cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
U.S. Patent No. US 9,732,062 B2 discloses Enasidenib or pharmaceutically acceptable salts and process for their preparation.
U.S. Patent No. US 9,738,625 B2 and PCT application WO 2016/126798 A1 discloses several crystalline forms of Enasidenib and Enasidenib mesylate and process for their preparation.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Enasidenib mesylate, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, solubility, dissolution etc. One crystalline form may give rise to thermal behavior different from that of another crystalline form.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new polymorphic forms or solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics. Since improved drug formulations are consistently sought, there is a need for additional crystalline forms of Enasidenib mesylate.
Therefore, the present application provides crystalline forms of Enasidenib mesylate and processes for making the same.
SUMMARY OF THE INVENTION
In the first embodiment, the present application provides a crystalline form V1a of Enasidenib mesylate.
In the second embodiment, the present application provides crystalline Form V1a of Enasidenib mesylate characterized by an X-ray powder diffraction pattern having peaks located at about 6.77 and 11.43± 0.2° 2?.
In the third embodiment, the present application provides a crystalline form V1a of Enasidenib mesylate characterized by X-ray powder diffraction substantially as illustrated by Fig.1.
In the fourth embodiment, the present application provides a process for preparing crystalline form V1a of Enasidenib mesylate, comprising the steps of:
a) providing a solution of Enasidenib mesylate in a solvent; and
b) isolating crystalline form V1a of Enasidenib mesylate by fast solvent evaporation;
In the fifth embodiment, the present application provides a crystalline form V1 of Enasidenib mesylate.
In the sixth embodiment, the present invention provides crystalline Form V1 of Enasidenib mesylate characterized by an X-ray powder diffraction pattern having peaks located at about 10.07 and 12.37± 0.2° 2?.
In the seventh embodiment, the present application provides a crystalline form V1 of Enasidenib mesylate characterized by X-ray powder diffraction substantially as illustrated by Fig.2.
In the eighth embodiment, the present application provides a process for preparing crystalline form V1 of Enasidenib mesylate comprising exposing crystalline form V1a of Enasidenib mesylate to ambient conditions.
In the ninth embodiment, the present application provides a pharmaceutical composition comprising crystalline form V1a of Enasidenib mesylate and one or more pharmaceutically acceptable excipients.
In the tenth embodiment, the present application provides a pharmaceutical composition comprising crystalline form V1 of Enasidenib mesylate and one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an illustration of powder X-ray diffraction (“PXRD”) pattern of crystalline form V1a of Enasidenib mesylate.
FIG. 2 is an illustration of powder X-ray diffraction (“PXRD”) pattern of crystalline form V1 of Enasidenib mesylate.
DESCRIPTION OF THE INVENTION
In the first embodiment, the present application provides a crystalline form V1a of Enasidenib mesylate.
In the second embodiment, the present invention provides crystalline Form V1a of Enasidenib mesylate characterized by an X-ray powder diffraction pattern having peaks located at about 6.77 and 11.43± 0.2° 2?.
In an aspect, the crystalline Form V1a of Enasidenib mesylate further characterized by an X-ray powder diffraction pattern having peaks located at about 8.81, 17.15, 17.60, 19.24, 19.90, 22.84 and 25.83± 0.2°2?.
In the third embodiment, the present application provides a crystalline form V1a of Enasidenib mesylate characterized by X-ray powder diffraction substantially as illustrated by Fig.1.
In the fourth embodiment, the present application provides a process for preparing crystalline form V1a of Enasidenib mesylate, comprising the steps of:
a) providing a solution of Enasidenib mesylate in a solvent; and
b) isolating crystalline form V1a of Enasidenib mesylate by fast solvent evaporation;
Any physical form of Enasidenib mesylate may be utilized for providing the solution of Enasidenib mesylate in step (a). In an aspect, crystalline Form 3 of Enasidenib mesylate that is reported in US 9,738,625 B2 may be used as an input for the preparation of crystalline form V1a of Enasidenib mesylate of the present application. The solvent that may be used is selected from alcohols such as methanol, ethanol, isopropanol, butanol, or mixtures thereof. Preferably the solvent used is methanol.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 150°C, less than about 130°C, less than about 100°C, less than about 70°C, less than about 40°C, less than about 20°C, less than about 0°C, or any other suitable temperatures, as long as a clear solution of Enasidenib mesylate is obtained without affecting its quality.
The solution obtained in step (a) may be optionally treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves isolating the crystalline Form V1a of Enasidenib mesylate, by fast solvent evaporation optionally under reduced pressure.
In the fifth embodiment, the present application provides a crystalline Form V1 of Enasidenib mesylate.
In the sixth embodiment, the present invention provides crystalline Form V1 of Enasidenib mesylate characterized by an X-ray powder diffraction pattern having peaks located at about 10.07 and 12.37± 0.2° 2?.
In an aspect, the crystalline Form V1 of Enasidenib mesylate further characterized by an X-ray powder diffraction pattern having peaks located at about 7.39, 11.44, 15.08, 25.91 and 26.41± 0.2°2?.
In the seventh embodiment, the present application provides a crystalline form V1 of Enasidenib mesylate characterized by X-ray powder diffraction substantially as illustrated by Fig.2.
In the eighth embodiment, the present application provides a process for preparing crystalline form V1 of Enasidenib mesylate comprising exposing crystalline form V1a of Enasidenib mesylate to ambient conditions.
In the ninth embodiment, the present application provides a pharmaceutical composition comprising crystalline form V1a of Enasidenib mesylate and one or more pharmaceutically acceptable excipients.
In the tenth embodiment, the present application provides a pharmaceutical composition comprising crystalline form V1 of Enasidenib mesylate and one or more pharmaceutically acceptable excipients.
In an aspect, the said crystalline form V1a and/or VI of Enasidenib mesylate may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
Enasidenib mesylate which may be used as the input in the process for preparation of the solid states of the present application can be prepared by any process known in the art.
The solid form of Enasidenib mesylate of the present application may be characterized by means of Powder X-ray Diffraction Pattern (PXRD). Other techniques, such as solid state NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) may also be used.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuKa radiation, having the wavelength 1.5406 Å and were obtained using Bruker D8 DISCOVER Powder X-ray Diffractometer. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the application in any manner.
DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The abbreviation “MC” mean moisture content. Moisture content can be conveniently measured, for example, by the Karl Fischer method.
“Crystalline form” as used herein refers to a solid state wherein the crystalline content with in the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (2 ?) of 7.7° to 8.1°”. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25oC and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
Fast solvent evaporation includes evaporation of solvent by simple drying, spray drying, rotavapor drying, thin film drying (e.g., agitated thin-film drying (ATFD)), rotational drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art optionally under reduced pressure.
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 unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
Where this document refers to a material, such as in this instance, Enasidenib mesylate and its solid state forms thereof by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in a Figure, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted in their positions, relative intensities and/or values due to a number of factors known to those of skill in the art.
In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure which uniquely define that solid state form, within any associated and recited margin of error, for purposes of identification.
As used herein, the term "room temperature" refers to a temperature of from about 20oC to about 35oC, from about 25oC to about 35oC, from about 25oC to about 30oC, or for example, about 25oC.
As used herein, the term "overnight" refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.
The "polymer" or “carrier” or “excipient”, as used herein interchangeably refer to any substance or mixture of substances which are pharmaceutically acceptable inactive ingredients.
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 CRYSTALLINE Form V1a OF ENASIDENIB MESYLATE
Enasidenib mesylate (10 gm) was dissolved in methanol (130 mL) in a round bottom flask at 350C. The solvent was evaporated under vacuum at 600C for 20 minutes and the solid obtained was dried under vacuum at 450C for about 24 hours to give crystalline form V1a of enasidenib mesylate. The Powder X-ray diffraction (PXRD) pattern of Enasidenib mesylate obtained herein is in accordance with Figure 1.

EXAMPLE 2: PREPARATION OF CRYSTALLINE FORM V1 of ENASIDENIB MESYLATE
Enasidenib mesylate obtained above is exposed to ambient conditions for 8 days to give crystalline form V1 of Enasidenib mesylate. The Powder X-ray diffraction (PXRD) pattern of Enasidenib mesylate obtained herein is in accordance with Figure 2.
,CLAIMS:Claims:

Claim 1: A process for preparing crystalline Form V1a of Enasidenib mesylate, comprising the steps of:
a) providing a solution of Enasidenib mesylate in a solvent; and
b) isolating crystalline form V1a of Enasidenib mesylate by fast solvent evaporation.

Claim 2: The process of claim 2, where solvent is selected from alcohols.

Claim 3: The process of claim 1, where isolation is done by fast solvent evaporation.

Claim 4: A process for preparing crystalline Form V1 of Enasidenib mesylate comprising exposing crystalline form V1a of Enasidenib mesylate to ambient conditions.

Claim 5: A pharmaceutical composition comprising crystalline Form VIa or crystalline Form VI and a pharmaceutically acceptable excipient.