SOLID STATE FORMS OF TIPIFARNIB AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Tipifamib, processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0002] Tipifamib chemical name is 6-[(A)-amino-(4-chlorophenyl)-(l-methyl-lH-imidazol-5- yl)methyl]-4-(3-chlorophenyl)-l-methylquinolin-2(lH)-one, having the following chemical structure:

[0003] Tipifamib is an oral nonpeptidomimetic famesyl transferase inhibitor used in both solid tumors and hematologic malignancies such as acute myeloid leukemia (AML) and other types of cancer. Tipifamib is also being investigated for the treatment of solid tumours, thyroid cancer, lymphomas, head and neck squamous cell carcinoma,

[0004] The compound is described as racemate and pure enantiomer by crystallization from 2- propanol in WO97/121701. W02018/103027 describes crystalline forms of Tipifamib.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis - “TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state ( ¹³ C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. [0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield 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 solid state forms of a pharmaceutically useful compound 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., a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemi cal/phy si cal stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Tipifarnib.

SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides solid state forms or crystalline polymorphs and amorphous form of Tipifarnib, processes for preparation thereof, and pharmaceutical compositions thereof. In particular, the present disclosure relates to solid state forms of Tipifarnib designated as Form TP1, Form TP2, Form TP3, Form TP4 and Form TP5 (defined herein).

[0009] The present disclosure provides any one of the above described crystalline polymorphs and amorphous form of Tipifarnib for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, preferably for the treatment of acute myeloid leukemia (AML) and other types of cancer, particularly solid tumours, thyroid cancer, lymphomas, and head and neck squamous cell carcinoma.

[0010] The present disclosure also encompasses the uses of any one of the above described crystalline polymorphs and amorphous form of Tipifarnib of the present disclosure for the preparation of pharmaceutical compositions and/or formulations.

[0011] In another aspect, the present disclosure provides pharmaceutical compositions comprising any one of the above described solid state forms or crystalline polymorphs and amorphous form of Tipifarnib according to the present disclosure.

[0012] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising any one of the above described solid state forms or crystalline polymorphs and amorphous form of Tipifarnib, or pharmaceutical compositions comprising the described crystalline polymorphs and amorphous form of Tipifarnib and at least one pharmaceutically acceptable excipient.

[0013] The present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions. The processes comprise combining any one of the above described solid state forms or crystalline polymorphs and amorphous form of Tipifarnib with at least one pharmaceutically acceptable excipient.

[0014] The solid state forms or crystalline polymorphs and amorphous form of Tipifarnib as defined herein and the pharmaceutical compositions or formulations of the solid state forms or crystalline polymorphs of Tipifarnib may be used as medicaments, particularly for the treatment of acute myeloid leukemia (AML) and other types of cancer, particularly solid tumours, thyroid cancer, lymphomas, and head and neck squamous cell carcinoma.

[0015] The present disclosure also provides methods of treating acute myeloid leukemia (AML) and other types of cancer, particularly solid tumours, thyroid cancer, lymphomas, and head and neck squamous cell carcinoma, comprising administering a therapeutically effective amount of any one of the solid state forms or crystalline polymorphs and amorphous form of Tipifarnib of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from acute myeloid leukemia (AML) and other types of cancer, particularly solid tumours, thyroid cancer, lymphomas, and head and neck squamous cell carcinoma, or otherwise in need of the treatment. [0016] The present disclosure also provides the use of any one of the solid state forms or crystalline polymorphs and amorphous form of Tipifarnib of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating acute myeloid leukemia (AML) and other types of cancer, particularly solid tumours, thyroid cancer, lymphomas, and head and neck squamous cell carcinoma.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Tipifarnib Form TP1.

[0018] Figure 2 shows a characteristic XRPD of Tipifarnib Form TP2.

[0019] Figure 3 shows a characteristic XRPD of Tipifarnib Form TP3.

[0020] Figure 4 shows a characteristic XRPD of Tipifarnib Form TP4.

[0021] Figure 5 shows a characteristic XRPD of Amorphous Tipifarnib.

[0022] Figure 6 shows a characteristic XRPD of Tipifarnib Form TP5.

[0023] Figure 7 shows a characteristic XRPD of Amorphous Tipifarnib hydrochloride.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0024] The present disclosure encompasses solid state forms of Tipifarnib, including crystalline forms and amorphous form, process for preparation thereof, and pharmaceutical composition comprising at least one of, or a combination of these solid state forms. Solid state properties of Tipifarnib can be influenced by controlling the conditions under which Tipifarnib crystalline forms and amorphous form thereof are obtained in solid form.

[0025] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a solid state form or crystalline polymorph of Tipifarnib described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject solid state form or crystalline polymorph of Tipifamib. In some embodiments of the disclosure, the described crystalline polymorphs of Tipifamib may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorphs of the same Tipifamib.

[0026] The solid state forms or crystalline polymorphs of Tipifamib as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.

[0027] A compound, solid state forms or crystalline polymorphs of Tipifamib as described in any aspect or embodiment of the present disclosure, may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms "chemically pure" or "purified" or "substantially free of any other compounds" refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. Particularly, the solid state forms or crystalline polymorphs of Tipifamib as described in any aspect or embodiment of the present disclosure is substantially free of the (S)-isomer of Tipifamib. A chemically pure or purified compound or a compound, or solid state forms or crystalline polymorphs of Tipifamib as described herein that is substantially free of any other compound will be understood to mean that it contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w), about 0.8% (w/w) or less, about 0.6% (w/w) or less about 0.4% (w/w) or less about 0.2% (w/w) or less or less, about 0.1% (w/w) or less or about 0% of any other compound as measured, for example, by HPLC. Alternatively, A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC. Thus, pure or purified Tipifamib described herein as substantially free of any compounds would be understood to contain greater than about 90% (w/w), greater than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about 98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2%, (w/w) greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Tipifamib. Alternatively, pure or purified Tipifamib described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2%, area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Tipifamib.

[0028] Depending on which other solid state forms or crystalline polymorphs a comparison is made, the solid state forms or crystalline polymorphs and amorphous form of Tipifamib of the present disclosure has advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability- such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.

[0029] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Tipifamib referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Tipifamib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0030] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline form of Tipifamib, relates to a crystalline form of Tipifamib which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would typically not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.

[0031] The term "solvate," as used herein and unless indicated otherwise, 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 a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0032] As used herein, and unless indicated otherwise, the term “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.

[0033] As used herein, and unless indicated otherwise, the term “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.

[0034] As used herein, the term "isolated" in reference to crystalline polymorph of Tipifamib of the present disclosure corresponds to a crystalline polymorph of Tipifamib that is physically separated from the reaction mixture in which it is formed.

[0035] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are measured using CuK a radiation, = 1.5418 A, at a temperature of 25 ± 3°C.

[0036] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT .” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C. [0037] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.

[0038] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, typically about 16 hours.

[0039] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar. [0040] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0041] The present disclosure comprises a crystalline polymorph of Tipifamib, designated Form TP1. The crystalline Form TP1 of Tipifarnib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 9.1, 10.8, 15.2, 24.9, and 29.0 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0042] Crystalline Form TP1 of Tipifamib may be further characterized by an X-ray powder diffraction pattern having peaks at 9.1, 10.8, 15.2, 24.9, and 29.0 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two or three additional peaks selected from 13.7, 17.9, and 22.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0043] Alternatively, crystalline Form TP1 of Tipifamib may be characterized by an X-ray powder diffraction pattern having peaks at 9.1, 10.8, 13.7, 15.2, 17.9, 22.0 24.9, and 29.0 degrees 2-theta ± 0.2 degrees 2-theta. [0044] In any aspect or embodiment of the disclosure, crystalline Form TP1 of Tipifamib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 5.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 12.0 to 13.0 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 16.0 to 17.0 degrees 2-theta ± 0.2 degrees 2-theta. Optionally, in any aspect or embodiment of the disclosure, crystalline Form TP1 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 5.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta, an absence of peaks at 12.0 to 13.0 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of peaks at 16.0 to 17.0 degrees 2-theta ± 0.2 degrees 2-theta

[0045] Crystalline Form TP1 of Tipifamib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.1, 10.8, 15.2, 24.9, and 29.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0046] In embodiment, Tipifamib Form TP1 may be characterized as a hydrate, in embodiment a monohydrate. Typically, Tipifarnib Form TP1 may contain from: about 2% to about 6.5% of water by weight, preferably from about 3% to about 5% of water by weight, more preferably from about 3.5% to about 4.5% of water by weight, or about 3.6% to about 4.4% of water by weight, or about 3.8% to about 4.4% of water by weight, about 3.7% of water by weight, or about 4.3% of water by weight, as determined for example by Karl Fischer or by other suitable techniques (the theoretical water content for Tipifamib monohydrate is about 3.8% by weight). [0047] In any aspect or embodiment of the present disclosure, Tipifamib Form TP1 is polymorphically pure. Optionally, Tipifamib Form TP1 may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0% (i.e. undetectable levels) of any other solid state forms of the subject compound (i.e. Tipifarnib) as measured, for example, by XRPD.

[0048] In any aspect or embodiment of the present disclosure, Tipifamib Form TP1 is chemically pure or substantially free of any other compounds. A chemically pure Form TP1 or purified Form TP1 or substantially free Form TP1 contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w), about 0.8% (w/w) or less, about 0.6% (w/w) or less about 0.4% (w/w) or less about 0.2% (w/w) or less or less, about 0.1% (w/w) or less or about 0% of any other compound as measured, for example, by HPLC. Thus, pure Form PT1 or purified Form PT1 or substantially free Form TP1 would be understood to contain greater than about 90% (w/w), greater than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about 98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2%, (w/w) greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Tipifarnib .

[0049] In any aspect or embodiment of the present disclosure, crystalline Tipifarnib form TP1 is isolated.

[0050] As discussed above, depending on which other solid state it is compared with, Tipifarnib Form TP1 according to the present disclosure may have advantageous properties as described above. Tipifarnib Form TP1 shows unexpected higher stability under heating and high humidity or other improved physical properties compared to other known crystalline polymorphs of Tipifarnib.

[0051] Tipifarnib Form TP1 as described in any aspect or embodiment of the present disclosure can be prepared by a process comprising a solvent/anti solvent crystallization. In any aspect or embodiment of the process, Tipifarnib Form TP1 is prepared by crystallization from a mixture of a solvent and an antisolvent, wherein the solvent is selected from: acetic acid ester, particularly an alkyl acetate, preferably a Ci to Cs acetic acid ester (i.e. a Ci to Cs alkyl acetate) (more preferably a C1-C4 acetic acid ester, i.e. a Ci to C4 alkyl acetate), preferably methyl acetate, ethyl acetate, vinyl acetate (typically methyl acetate); or the solvent may be dichloromethane. In any aspect or embodiment of the process the antisolvent is selected from: an aliphatic or cyclic alkane (preferably a C5-C10 aliphatic or a C5-C10 cyclic alkane), particularly n-heptane, n-pentane, n-hexane, or combinations thereof (typically n-heptane), or the antisolvent may be methyl tert butyl ether (MTBE).

[0052] In any aspect or embodiment of the present invention, Tipifarnib Form TP1 can be prepared by a process comprising crystallization from a solvent which is methyl acetate, ethyl acetate, vinyl acetate or dichloromethane, or a combination thereof, typically methyl acetate, and an antisolvent which is n-heptane, n-pentane, n-hexane or MTBE. In any aspect or embodiment of the present invention, Tipifarnib Form TP1 can be prepared by a process comprising crystallization from methyl acetate and n-heptane. [0053] According to any aspect or embodiment of the present disclosure, crystalline Form TP1 may be prepared by a process comprising: a) combining a solution of Tipifamib in a solvent, particularly an acetic acid ester or dichloromethane or combinations thereof, with an antisolvent (particularly an aliphatic or cyclic alkane, or MTBE); b) optionally isolating the Tipifarnib Form TP1; and c) optionally drying.

[0054] Preferably, the solvent in step (a) is an acetic acid ester or di chloromethane or a combination thereof; and the antisolvent is aliphatic or cyclic or MTBE. According to any embodiment of the process, the solvent in step (a) is selected from: an alkyl acetate, a Ci-Cs acetic acid ester (i.e. a Ci to Cs alkyl acetate) and preferably a Ci to C4 acetic acid ester (i.e. a Ci to C4 alkyl acetate), or dichloromethane; and the antisolvent is a C5-C10 aliphatic or a C5-C10 cyclic alkane or MTBE. In any embodiment of the process, the acetic acid ester in step a) is preferably selected from methyl acetate, ethyl acetate, vinyl acetate, and particularly methyl acetate. The aliphatic alkane can be preferably selected from n-heptane, n-pentane or n-hexane. According to any embodiment of the process, the solvent in step (a) is preferably selected from methyl acetate, ethyl acetate, vinyl acetate or dichloromethane; and the antisolvent is preferably selected from, n-heptane, n-pentane, n-hexane, or MTBE. Particularly, in step (a) the solvent is methyl acetate, and the antisolvent is n-heptane.

[0055] In any aspect or embodiment of the process for preparing Tipifamib Form TP1, the solvent may be used an amount of about 80 vol to about 200 vol, about 100 vol to about 180 vol and preferably about 100 vol to about 150 vol relative to Tipifarnib. In any aspect or embodiment of the process for preparing Tipifarnib Form TP1, when the solvent is methyl acetate, the solvent may be used in an amount of about 100 vol to about 150 vol, about 110 to about 140 vol, about 110 to about 130 vol, or about 120 vol. The antisolvent may be used in an amount of about 200 vol to about 300 vol, and preferably about 200 vol to about 250 vol, relative to Tipifarnib. When the antisolvent is n-heptane, the antisolvent may be used in an amount of about 200 vol to about 250 vol, about 230 vol to about 250 vol, or about 240 vol relative to Tipifamib. The volume ratio of solvent to antisolvent in step (a) may be: about 1 : 1 to about 1 :20, about 1 : 1 to about 1 : 15, about 1 : 1 to about 1 : 10, about 1 : 1 to about 1 :5, and/or about 1 :2. Particularly, when the solvent is methyl acetate and the antisolvent is n-heptane, the volume ratio of methyl acetate to n-heptane may be: about 1 : 1 to about 1 : 15, about 1 : 1 to about 1 : 10, about 1 : 1 to about 1 :5 or about 1 :2.

[0056] In any aspect or embodiment of the process for preparing Tipifamib Form TP1, the mixture of Tipifamib in the solvent is preferably heated to a temperature of about 30°C to about 60°C, in embodiments about 40°C to about 60°C, and in other embodiments to about 50°C to about 55°C, preferably with stirring. The resulting solution may be optionally filtered in order to remove undissolved particles. The filtration can be carried out at elevated temperature (such as the temperature of the mixture of Tipifamib in the solvent as described above).

[0057] Step (a) may comprise addition of the antisolvent (e.g. n-heptane, n-pentane, n-hexane or MTBE, typically n-heptane) to the solution of Tipifamib, or, preferably, the Tipifamib solution (e.g. in methyl acetate) is added the antisolvent. In any embodiment of the process, step (a) may comprise adding the solution of Tipifamib in the solvent to a pre-cooled antisolvent, preferably wherein the antisolvent is cooled to about -40°C to about 0°C, about -30°C to about -10°C, or about -20°C. The addition may be carried out over a period of about 1 to about 30 minutes, about 1 to about 20 minutes, about 1 to about 10 minutes, or about 1 to about 5 minutes, or about 1 minute.

[0058] According to any embodiment of the above processes for preparing Form TP1, the reaction mixture comprising Tipifamib, solvent and antisolvent, may be maintained at about - 40°C to about 0°C, or about -30°C to about -10°C, or about -20°C. The mixture may be maintained at this temperature for about 2 to about 30 hours, about 5 to about 20 hours, about 2 to about 18 hours, or about 16 hours, preferably with stirring. In any embodiment, the reaction mixture may be further maintained at: about 10°C to about 40°C, about 20°C to about 30°C, or about 25°C for about 5 to about 60 minutes, about 10 to about 40 minutes, or about 30 minutes, preferably with stirring.

[0059] In any embodiment of the above processes for preparing Form TP1, step (b) may include isolation of Tipifamib Form TP1. The isolation may be carried out by any suitable means, such as by centrifuge, decantation, or by filtration, preferably by filtration. Preferably, the filtration is carried out at temperature of about 10°C to about 40°C, preferably about 20°C to about 30°C or about 25°C. Following the isolation, the product may be washed, and optionally dried. Drying may be done by nitrogen or air or under vacuum. Drying may be performed at a temperature of about 50°C to about 70°C, in embodiment about 60°C for about 1 to 48 hours, in embodiment 24 hours. When the drying is carried out under vacuum, a reduced pressure of: about 1 or about 200 mbar, about 1 to about 100 mbar, about 1 to about 50 mbar, and particularly about 5 to about 40 mbar or more particularly, about 20 mbar, may be used.

[0060] The above described processes for preparing Form TP1 of Tipifarnib may further comprise combining the Form TP1 of Tipifarnib with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation or dosage form.

[0061] The present disclosure comprises a crystalline polymorph of Tipifarnib, designated Form TP2. The crystalline Form TP2 of Tipifarnib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 6.5, 9.9, 15.6, 17.8 and 26.6 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0062] Crystalline Tipifarnib Form TP2 may be further characterized by an X-ray powder diffraction pattern having peaks at 6.5, 9.9, 15.6, 17.8 and 26.6 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three, four or five additional peaks selected from 13.0, 19.6, 25.2, 25.8 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0063] Alternatively, crystalline Tipifarnib Form TP2 may be characterized by an X-ray powder diffraction pattern having peaks at 6.5, 9.9, 13.0, 15.6, 17.8, 19.6, 25.2, 25.8, 26.6 and 29.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0064] In any aspect or embodiment of the disclosure, crystalline Form TP2 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 3.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 7.0 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 10.5 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta. Optionally, in any aspect or embodiment of the disclosure, crystalline Form TP2 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 3.0 to 6.0 degrees 2-theta ± 0.2 degrees 2-theta, an absence of peaks at 7.0 to 8.0 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of peaks at 10.5 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0065] Crystalline Tipifarnib Form TP2 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 6.5, 9.9, 15.6, 17.8 and 26.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof. [0066] In embodiment Tipifarnib Form TP2 may be characterized as acetic acid solvate, in embodiment mono acetic acid solvate. Typically, Tipifarnib Form TP2 may contain from about 9% to about 13% of acetic acid by weight, preferably from about 10% to about 12% by weight, more preferably from about 10.5% to about 12% by weight, about 10.8% to about 11.5% by weight, or about 11% by weight, as determined for example by TGA or by other suitable techniques (the theoretical acetic acid content for mono acetic acid solvate is about 10.9% by weight).

[0067] In any aspect or embodiment of the present disclosure, Tipifarnib Form TP2 is polymorphically pure. Optionally, Tipifarnib Form TP2 may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0% (i.e. undetectable levels) of any other solid state forms of the subject compound (i.e. Tipifarnib) as measured, for example, by XRPD.

[0068] In any aspect or embodiment of the present disclosure, crystalline Tipifarnib form TP2 is isolated.

[0069] The present disclosure comprises a crystalline polymorph of Tipifarnib, designated Form TP3. The crystalline Form TP3 of Tipifarnib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 8.1, 9.8, 23.1, 28.3 and 31.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0070] Crystalline Tipifarnib Form TP3 may be further characterized by an X-ray powder diffraction pattern having peaks at 8.1, 9.8, 23.1, 28.3 and 31.7 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two, three or four additional peaks selected from 11.1, 15.4, 24.3 and 35.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0071] Alternatively, crystalline Tipifarnib Form TP3 may be characterized by an X-ray powder diffraction pattern having peaks at 8.1, 9.8, 11.1, 15.4, 23.1, 24.3, 28.3, 31.7 and 35.6 degrees 2- theta ± 0.2 degrees 2-theta.

[0072] In any aspect or embodiment of the disclosure, crystalline Form TP3 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 3.0 to 6.2 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 8.6 to 9.3 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 11.6 to 12.5 degrees 2-theta ± 0.2 degrees 2-theta. Optionally, in any aspect or embodiment of the disclosure, crystalline Form TP3 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 3.0 to 6.2 degrees 2-theta ± 0.2 degrees 2-theta, an absence of peaks at 8.6 to 9.3 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of peaks at 11.6 to 12.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0073] Crystalline Tipifarnib Form TP3 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.1, 9.8, 23.1, 28.3 and 31.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0074] In any embodiment of the disclosure, Tipifarnib Form TP3 may be characterized as ethyl formate solvate. Optionally, Tipifarnib Form TP3 may be characterized as a hemi ethyl formate solvate. According to any embodiment of the present disclosure, Tipifarnib Form TP3 may contain: about 6.0 to about 12.0 wt%, about 7.5% to about 11.0 wt%, about 8.0 to about 10.0 wt%, about 8.5 to about 9.5 wt%, about 9.0 to about 9.3 wt% of ethyl formate, or about 9.2 wt% of ethyl formate.

[0075] In any aspect or embodiment of the present disclosure, crystalline Tipifarnib form TP3 is isolated.

[0076] The present disclosure comprises a crystalline polymorph of Tipifarnib, designated Form TP4. The crystalline Form TP4 of Tipifarnib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 13.3, 17.8, 19.2 and 22.3 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0077] Crystalline Tipifarnib Form TP4 may be further characterized by an X-ray powder diffraction pattern having peaks at 13.3, 17.8, 19.2 and 22.3 degrees 2-theta ± 0.2 degrees 2- theta, and also having any one, two or three additional peaks selected from 8.8, 14.3, and 22.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0078] Alternatively, crystalline Tipifarnib Form TP4 may be characterized by an XRPD pattern having peaks at 8.8, 13.3, 14.3, 17.8, 19.2, 22.3 and 22.8 degrees 2-theta ± 0.2 degrees 2-theta. [0079] In any aspect or embodiment of the disclosure, crystalline Form TP4 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 3.0 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 9.5 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta. Optionally, in any aspect or embodiment of the disclosure, crystalline Form TP4 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 7.0 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of peaks at 9.5 to 12.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0080] Crystalline Tipifarnib Form TP4 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 13.3, 17.8, 19.2 and 22.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0081] In embodiment Tipifarnib Form TP4 may be characterized as 1,4-Dioxane solvate and Cyclopentyl methyl ether solvate.

[0082] The present disclosure comprises amorphous Tipifarnib. Amorphous Tipifarnib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an absence of crystalline peaks in the X-ray powder diffraction pattern; and combinations of these data. Optionally, amorphous Tipifarnib may be characterized by having an X-ray powder diffraction pattern showing a halo between 14.0 and 30.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0083] The present disclosure comprises a crystalline polymorph of Tipifarnib, designated Form TP5. The crystalline Form TP5 of Tipifarnib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 5.7, 8.0, 16.6, and 20.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0084] Crystalline Form TP5 of Tipifarnib may be further characterized by an X-ray powder diffraction pattern having peaks at 5.7, 8.0, 16.6 and 20.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two or three additional peaks selected from 18.3, 22.3, and 26.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0085] Alternatively, crystalline Form TP5 of Tipifarnib may be characterized by an X-ray powder diffraction pattern having peaks at 5.7, 8.0, 16.6, 18.3, 20.4, 22.3 and 26.3 degrees 2- theta ± 0.2 degrees 2-theta.

[0086] In any aspect or embodiment of the disclosure, crystalline Form TP5 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having: an absence of peaks at 3.0 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta, and/or an absence of peaks at 8.5 to 10.0 degrees 2-theta ± 0.2 degrees 2-theta. Optionally, in any aspect or embodiment of the disclosure, crystalline Form TP5 of Tipifarnib may be additionally characterized by an X-ray powder diffraction pattern having an absence of peaks at 3.0 to 4.5 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of peaks at 8.5 to 10.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0087] Crystalline Form TP5 of Tipifarnib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.7, 8.0, 16.6, and 20.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.

[0088] In embodiment, Tipifarnib Form TP5 may be characterized as a hydrate, in embodiment a monohydrate. Typically, Tipifarnib Form TP5 may contain from: about 2% to about 6.5% of water by weight, preferably from about 3% to about 5.2% of water by weight, more preferably from about 3.5% to about 5.0% of water by weight, about 3.6% to about 4.9% of water by weight, about 3.7% to about 4.7% of water by weight, about 3.8% of water by weight wt%, or about 4.7% of water by weight, determined for example by Karl Fischer, or by other suitable techniques (the theoretical water content for monohydrate is about 3.8% by weight).

[0089] In any aspect or embodiment of the present disclosure, Tipifarnib Form TP5 is polymorphically pure. Optionally, Tipifarnib Form TP5 may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0% (i.e. undetectable levels) of any other solid state forms of the subject compound (i.e. Tipifarnib) as measured, for example, by XRPD.

[0090] In any aspect or embodiment of the present disclosure, Tipifarnib Form TP5 is chemically pure or substantially free of any other compounds. A chemically pure Form TP5 or purified Form TP5 or substantially free Form TP5 contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w), about 0.8% (w/w) or less, about 0.6% (w/w) or less about 0.4% (w/w) or less about 0.2% (w/w) or less or less, about 0.1% (w/w) or less or about 0% of any other compound as measured, for example, by HPLC. Thus, pure Form PT5 or purified Form PT5 or substantially free Form TP5 would be understood to contain greater than about 90% (w/w), greater than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about 98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2%, (w/w) greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Tipifarnib.

[0091] In any aspect or embodiment of the present disclosure, crystalline Tipifarnib form TP5 is isolated.

[0092] As discussed above, depending on which other solid state it is compared with, Tipifarnib Form TP5 according to the present disclosure may have advantageous properties as described above. Tipifarnib Form TP5 shows unexpected higher stability under high humidity or other improved physical properties compared to other known crystalline polymorphs of Tipifarnib. [0093] Tipifarnib Form TP5 as described in any aspect or embodiment of the present disclosure can be prepared by a process comprising crystallization of Tipifarnib in water.

[0094] According to any aspect or embodiment of the present disclosure, crystalline Form TP5 may be prepared by a process comprising: a) combining a solution of Tipifarnib in water, optionally with base; b) optionally isolating the Tipifarnib Form TP5; and c) optionally drying.

[0095] Tipifarnib used in step (a) may be free base, salt or co-crystal, preferably salt, preferably amorphous salt, preferably Tipifarnib hydrochloride, preferably amorphous Tipifarnib hydrochloride.

[0096] The present disclosure further includes amorphous Tipifarnib hydrochloride. The amorphous Tipifarnib hydrochloride may be characterized by a powder X-ray diffraction pattern substantially as depicted in Figure 7.

[0097] Optionally, the process may comprise: a) combining an acid addition salt of Tipifarnib (preferably Tipifarnib Hydrochloride) with water, optionally heating the mixture, and combining the mixture with a base, preferably an organic base; b) optionally isolating the Tipifarnib Form TP5; and c) optionally drying.

[0098] In any aspect or embodiment of the above processes for preparing Tipifarnib Form TP5, the water in step (a) of the processes may be used in an amount of about 80 vol to about 200 vol, about 90 to about 150 vol, about 90 to about 110 vol, or about 100 vol relative to the Tipifarnib or Tipifarnib acid addition salt. [0099] In any aspect or embodiment of the processes for preparing Tipifamib Form TP5, the mixture of Tipifamib or Tipifarnib acid addition salt in water may be heated to a temperature of about 30°C to about 60°C, in embodiments about 40°C to about 60°C, and in other embodiments to about 50°C to about 55°C, preferably with stirring.

[00100] The base in step (a) may be an organic base, optionally wherein the base is an organic amine, optionally wherein the base is selected from triethyl amine, diethyl amine, ethyl amine, piperidine, pyrrolidine or 4-dimethylaminopyridine, and preferably triethyl amine. In any aspect or embodiment of the processes, the base may be combined with the mixture of Tipifamib or Tipifamib acid addition salt at a temperature of about 35 to about 20°C, about 30°C to about 20°C, or about 25 °C. Accordingly, the mixture of Tipifamib or Tipifamib acid addition salt may be first heated to a temperature of: about 30°C to about 60°C, about 40°C to about 60°C, or about 50°C to about 55°C, and then cooled to a temperature of about: 35 to about 20°C, about 30°C to about 20°C, or about 25°C prior to combining with the base. In any embodiment of the processes, the base may be added to the mixture of Tipifarnib or Tipifamib acid addition salt in water at a temperature of: about 35 to about 20°C, about 30°C to about 20°C, or about 25°C. The addition may be carried out over a period of about 1 to about 10 minutes, about 1 to about 5 minutes or about 1 to about 2 minutes.

[00101] The resulting mixture of step (a) may be maintained at a temperature of: about 40°C to about 20°C, or about 30°C to about 20°C, or about 25°C. The mixture may be maintained at this temperature for about 10 minutes to about 240 minutes, about 20 to about 120 minutes, about 20 to about 100 minutes, about 30 to about 80 minutes, or about 30 to about 60 minutes, preferably with stirring.

[00102] In any embodiment of the above processes for preparing Form TP5, step (b) may include isolation of Tipifarnib Form TP5. The isolation may be carried out by any suitable means, such as by centrifuge, decantation, or by filtration, preferably by filtration. Preferably, the filtration is carried out at temperature of about 10°C to about 40°C, preferably about 20°C to about 30°C. Following the isolation, the product may be washed, and optionally dried. Drying may be done by nitrogen or air or under vacuum. Drying may be performed at a temperature of about 20°C to about 30°C, or about 25°C, preferably for about 1 to 48 hours, in embodiment 1 to 2 hours. When the drying is carried out under vacuum, a reduced pressure of: about 1 or about 200 mbar, about 1 to about 100 mbar, about 1 to about 50 mbar, and particularly about 5 to about 40 mbar or more particularly, about 20 mbar, may be used.

[00103] The above described processes for preparing Form TP5 of Tipifamib may further comprise combining the Form TP5 of Tipifarnib with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical formulation or dosage form.

[00104] The above crystalline forms and amorphous form can be used to prepare other crystalline polymorphs of Tipifamib.

[00105] The present disclosure provides any one or combination of the above described solid state forms or crystalline forms and amorphous form of Tipifarnib for use in the preparation of pharmaceutical compositions and/or formulations comprising Tipifarnib and/or polymorphs thereof.

[00106] The present disclosure also encompasses the use of any one or combination of the above described solid state forms or crystalline polymorphs or amorphous form of Tipifamib of the present disclosure for the preparation of pharmaceutical compositions of amorphous and crystalline forms of Tipifamib and/or crystalline polymorphs thereof.

[00107] The present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions. The processes comprise combining any one or combination of the above described solid state forms, crystalline polymorphs or amorphous form of Tipifarnib of the present disclosure with at least one pharmaceutically acceptable excipient.

[00108] The solid state forms, crystalline polymorphs, or amorphous form of Tipifarnib and the pharmaceutical compositions of Tipifamib of the present disclosure can be used as medicaments, particularly in the treatment of acute myeloid leukemia (AML) and other types of cancer, particularly solid tumours, thyroid cancer, lymphomas, and head and neck squamous cell carcinoma.

[00109] The present disclosure also provides methods of treating acute myeloid leukemia and other types of cancer, particularly solid tumours, thyroid cancer, lymphomas, and head and neck squamous cell carcinoma, comprising administering a therapeutically effective amount of solid state forms or crystalline polymorphs of Tipifarnib of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject in need of the treatment.

[00110] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.

Powder X-Ray Diffraction (XRD) Method

[00111] X-ray diffraction was performed on X-Ray powder diffractometer: Bruker D8 Advance; CuK radiation ( = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

Measurement parameters:

Scan range: 2 - 40 degrees 2-theta;

Scan mode: continuous;

Step size: 0.05 degrees;

Time per step: 0.5 s;

Sample spin: 30 rpm;

Sample holder: PMMA specimen holder ring.

Preparation of starting material

[00112] The starting material Tipifamib can be prepared following the process described in PCT application WO97/121701 (compound 75).

Example 1. Preparation of Tipifarnib Form TP1

[00113] Tipifarnib (0.1 grams) was dissolved in methyl acetate (12 mL) at 50-55°C. The clear solution was added dropwise (in one portion) into precooled n-Heptane (24 ml) at -20°C and maintained at -20°C for about 16 hours, with stirring. The reaction mass was further kept at room temperature (about 25°C) for about 30 minutes, under stirring before isolation. The obtained solid was filtered and analyzed by XRD to produce Tipifamib designated Form TP1 characterized by XRPD in figure 1.

Example 2. Preparation of Tipifarnib Form TP2

[00114] Tipifarnib (0.5 grams) was dissolved in Acetic acid (1 mL) at 25-30°C. The clear solution was added dropwise (one portion) into precooled mixture of methyl tert-butyl ether MTBE (6 ml) and n-Heptane (6ml) at -20°C and maintained at -20°C for about 20 hours, with stirring. The reaction mass was further kept at room temperature (about 25°C) for about 30 minutes, under stirring before isolation. The obtained solid was filtered, dried in Vacuum oven at 60°C for 2 hours and analyzed by XRD to produce Tipifarnib designated Form TP2 characterized by XRPD in figure 2.

Example 3. Preparation of Tipifarnib Form TP3

[00115] Tipifarnib (0.15 grams) was dissolved in ethyl formate (2.25 mL) at 50-54°C. The clear solution was immediately cool down to -20°C, and maintained at this temperature for about 15 hours, under stirring. The reaction mass was further kept at room temperature (about 25°C) for about 30 minutes, with stirring before isolation. The obtained solid was isolated by filtration and analyzed by XRD to produce Tipifarnib designated Form TP3 characterized by XRPD in figure 3.

Example 4. Preparation of Tipifarnib Form TP4

[00116] Tipifarnib (0.03 grams) was dissolved in 1,4-Dioxane (0.6 mL) at 50°C. The clear solution was added dropwise (one portion) into precooled Cyclopentyl methyl ether (CPME, 6 ml) at -20°C and maintained at -20°C for about 20 hours, under stirring. The reaction mass was further kept at 25°C for 30 minutes, under stirring before isolation. The obtained solid was filtered and analyzed by XRD to produce Tipifarnib designated Form TP4 characterized by XRPD in figure 4.

Example 5. Preparation of Amorphous Tipifarnib

[00117] Tipifarnib (2.5 grams) was dissolved in tetrahydrofuran (120 mL) at 60°C. The solution was filtered through 0.45-micron filter and subjected to distillation under reduced pressure using rotary evaporator at 60°C for 60 minutes. The obtained solid was isolated and analyzed by XRD to produce amorphous Tipifarnib characterized by XRPD in figure 5.

Example 6. Preparation of Amorphous Tipifarnib hydrochloride

[00118] Tipifarnib (1 gram) was dissolved in Dichloromethane (15 mL) at 35°C to obtain clear solution. The clear solution was cooled down to 25°C in about 5-10 minutes and HC1 solution in isopropanol (IP A) (about 18%, 0.5 ml) was added dropwise. The mixture was maintained under stirring for about 2 hour at 25 °C and a hazy solution was obtained. Heptane (30ml) was added into the hazy solution and the mixture maintained under stirring for about 2 hour at 25 °C. The reaction mixture was filtered, dried under vacuum for about 10 minutes and analyzed by XRPD to obtain amorphous Tipifarnib Hydrochloride salt (figure 7).

Example 7. Preparation of Tipifarnib Form TP5

[00119] Amorphous Tipifarnib Hydrochloride (0.3 grams, prepared following example 6) was dissolved in water (30 mL) at 50-55°C to obtain a milky solution. The solution was cooled to 25°C in about 10-15 minutes and Triethyl amine (0.6 ml) was added dropwise (in about 2 minutes) and the mixture was maintained under stirring for about 30 minutes to 1 hour at 25 °C. The obtained solid was filtered, dried under vacuum for about 1-2 hours at room temperature, and analyzed by XRPD to obtained crystalline form designated as Form TP5 (figure 6).