DESC:POLYMORPHS OF NERATINIB MALEATE

FIELD OF THE APPLICATION
The present application relates to a novel crystalline form of Neratinib Maleate and processes for preparation thereof.
The drug compound having the adopted name “Neratinib Maleate” and it has chemical name: (E)-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate; and a structure depicted by Formula I.

Formula I
International Patent Application Publication Nos. WO2005034955A1, WO2009052264A2, WO2016110270A1, WO2018005418A1, WO2018134843A1, and WO2018189695 A1 which are incorporated herein in their entirety reported Neratinib and its maleate salts, and their crystalline forms. Neratinib maleate is a kinase inhibitor and it is approved under the brand name of NERLYNX® by US FDA for the treatment of adult patients with early stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Neratinib maleate, 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 solubility.
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 Neratinib maleate.
The present invention describes a novel polymorph of Neratinib maleate that helps to meet aforementioned and other needs.
The Neratinib Maleate solid state forms thereof according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, morphology, stability-such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, and advantageous processing and handling characteristics such as compressibility or bulk density.
The present invention provides novel crystalline Form SS1 of Neratinib maleate.

SUMMARY OF THE INVENTION
In the first embodiment, the present application provides crystalline Form SS1 of Neratinib maleate (Formula I).
In the second embodiment, the present invention relates to crystalline Form SS1 of Neratinib maleate characterized by PXRD having at least the characteristic peaks located at about 9.34, 14.04, 23.67 and 24.91 ± 0.2 of 2?.
In the third embodiment, the present application provides crystalline Form SS1 of Neratinib maleate which can be characterized by its PXRD pattern as illustrated by Figure 1.
In the fourth embodiment, the present application provides processes for preparing crystalline Form SS1 of Neratinib maleate, comprising the steps of:
a) providing a mixture of Neratinib maleate in formic acid; optionally in presence of suitable solvent;
b) isolating the crystalline Form SS1 of Neratinib maleate.

BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an illustration of powder X-ray diffraction (“PXRD”) pattern of Crystalline Form SS1 of Neratinib Maleate according to Example 1.

DESCRIPTION OF THE INVENTION
In the first embodiment, the present application provides crystalline Form SS1 of Neratinib maleate (Formula I) which can be characterized by its PXRD pattern as illustrated by Figure 1.

Formula I

In the second embodiment, the present invention relates to crystalline Form SS1 of Neratinib maleate characterized by PXRD having at least the characteristic peaks located at about 9.34, 14.04, 23.67 and 24.91 ± 0.2 of 2?.
In yet another aspect, the present invention relates to crystalline Form SS1 of Neratinib maleate further characterized by PXRD having the characteristic peaks located at about 9.34, 14.04, 23.67 and 24.91 ± 0.2 of 2?.
In the third embodiment, the present application provides crystalline Form SS1 of Neratinib maleate which can be characterized by its PXRD pattern as illustrated by Figure 1.
In the fourth embodiment, the present application provides processes for preparing crystalline Form SS1 of Neratinib maleate, comprising the steps of:
a) providing a mixture of Neratinib maleate in formic acid; optionally in presence of suitable solvent;
b) isolating the crystalline Form SS1 of Neratinib maleate.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing Neratinib maleate that is obtained in the course of its synthesis; or
ii) dissolving Neratinib maleate in a suitable solvent.
Any physical form of Neratinib maleate may be utilized in step (a) of the process embodiments herein above.
The Nerainib maleate of step a) is 1:1 salt.
The mixture of step a) comprises formic acid either employed alone or as a mixture in a suitable solvent.
The amount of formic acid added in suitable solvent can vary from 1:1 (v/v) to 1:20 (v/v).
In a preferred embodiment, the ratio of formic acid to suitable solvent ranges between 1:5 (v/v) to 1:10 (v/v).
The reaction mixture of step a) can be heated to dissolution temperature as long as the stability of Neratinib maleate is not compromised and a substantially clear solution is obtained. For example dissolution temperature may range from about 20oC to about reflux temperature of the solvent.
The solution obtained in step (a) may be optionally filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, micron filter, centrifugation, decantation, and any other techniques known in the art. 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 precipitation of solid.
Step (b) involves isolating the crystalline Form SS1 of Neratinib maleate.
The isolation of crystalline Form SS1 of Neratinib maleate may be induced by using conventional techniques known in the art. For example, useful techniques include but are not limited to, partial evaporation, cooling, stirring, shaking, or combining with a suitable anti-solvent, adding seed crystals, or the like. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure.
In a preferred embodiment, anti-solvent is added for initiating crystallization.
Suitable solvents and/or anti-solvents employed in the process for preparation of crystalline Form SS1 of Neratinib Maleate include but are not limited to: alcoholic solvents such as methanol, 2-methoxyethanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ethers such as diethyl ether, methyl tert-butyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as hexane, heptane and the like; nitriles such as acetonitrile, propionitrile and the like; polar aprotic solvents like DMSO, DMF,DMA and the like; water and any mixtures of two or more thereof.
Appropriate solvents or anti-solvent can be chosen from the above mentioned list of solvents by a skilled person based on solubility test, volatility etc.
In a preferred embodiment, formic acid alone is used as a solvent in step a) and methyl tert-butyl ether is employed as an anti-solvent in step b).
The recovery of crystalline Form SS1 of Neratinib maleate can be done by using the processes known in the art like decantation, centrifugation, gravity filtration, suction filtration or other techniques specific to the equipment used.
The resulting compound may be optionally further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the crystalline Neratinib maleate salt is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
Once obtained, crystals of Neratinib maleate may be used as the nucleating agent or “seed” crystals for subsequent crystallizations of Neratinib maleate from solutions.
In an aspect, the present application provides pharmaceutical formulations comprising crystalline Form SS1 of Neratinib maleate together with one or more pharmaceutically acceptable excipients. Neratinib maleate Form SS1 together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; 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.
Pharmaceutically acceptable excipients that are useful in the present application are the same as defined above.
The pharmaceutical dosage form according to the present invention may be is coated with one or more coating materials or uncoated. The coating materials are not particularly limited and are known to the person skilled in the art.
The pharmaceutical dosage form according to the present invention can further comprise additional excipients and adjuvants, which are pharmaceutically acceptable and general coating materials, which are preferably applied as a coating to the pharmaceutical dosage form of the present invention. Such further excipients and adjuvants are known to the person skilled in the art.
The pharmaceutical compositions of the present invention are generally administered orally to patients, which include, but are not limited to, mammals, for example, humans, in the form of, for example, a hard or soft gelatin capsule, a tablet, a caplet, pills, granules or a suspension. The pharmaceutical dosage form can be prepared by methods known in the art, such as direct compression or wet granulation or direct compression. The compression of the blend to tablet cores can be carried out using a conventional tableting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent.
Neratinib or its maleate salt 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 Neratinib or its maleate salt 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 a Bruker AXS D8 Advance 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.
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).
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%.
A solid state form (or a polymorph) may be referred to herein as polymorphically pure or substantially free of any other solid state (or polymorphic) forms. The term “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, about 0.5% or less, or about 0% of any other forms of the subject compound as measured, for example by PXRD.
The expression “wet crystalline form” refers to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.
The expression “dry crystalline form” refers to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, etc.
The term “solvate” refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as “hydrate”. The solvent in a solvate may be present in either stoichiometric or in a non-stoichiometric amount.
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.
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, Neratinib or its maleate salt, and their 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.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
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.
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 SS1 OF NERATINIB MALEATE
Neratinib maleate (1.3 g) was dissolved in formic acid (5 mL) at ~25oC for about 30 minutes. To the above mixture, methyl tert-butyl ether (45 mL) was slowly added at the room temperature and mixture was stirred for about 5 hours. The obtained solid was isolated by filtration, grinded and dried to afford the title compound.
,CLAIMS:We/I Claim

Claim 1: A process for preparing crystalline Form SS1 of Neratinib maleate, comprising the steps of:
a) providing a mixture of Neratinib maleate in formic acid; optionally in presence of suitable solvent;
b) isolating the crystalline Form SS1 of Neratinib maleate.

Claim 2: The process of claim 1 wherein the suitable solvent in step a) is selected from alcohols, ketones, esters, halogenated hydrocarbons; nitriles polar aprotic solvents like DMSO, DMF,DMA.

Claim 3: The process of Claim 1, wherein isolation in step b) is done by addition of anti-solvent.

Claim 4: The process of Claim 3, wherein the suitable anti-solvent is methyl tert-butyl ether

Claim 5: A pharmaceutical composition comprising crystalline Form SS1 of Neratinib maleate and suitable pharmaceutically acceptable excipients.