Polymorphs of lorlatinib

Abstract

The present invention relates to novel polymorphs of Lorlatinib, designated as Lorlatinib Form C1, Form C2, Form C3 and Form C4 and processes for the preparation thereof.

Description

[0001] POLYMORPHS OF LORLATINIB

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel polymorphs of Lorlatinib and processes for the preparation thereof.

[0004] BACKGROUND OF INVENTION

[0005] Lorlatinib is chemically known as (10R)-7-amino-12-fhioro2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,l 1] benzoxadiaza cyclo tetradecine-3 -carbonitrile represented as shown in Structure-I.

[0006]

[0007] Structure-I

[0008] Lorlatinib is approved by USFDA in November 2018 for treatment of lung cancer. It is an orally administered inhibitor of anaplastic lymphoma kinase (ALK) and is indicated for the treatment of lung cancer specifically Non-Small Cell Lung Cancer (NSCLC).

[0009] US 8680111 B2 discloses a preparation of Lorlatinib as an amorphous solid.

[0010] US 9637500 B2 discloses various polymorphs such as acetic acid solvate Form 3, Hydrate Form 1 and Hydrate Form 2.US 10420749 B2 discloses preparation of an anhydrous crystalline form of Lorlatinib free base Form 7.

[0011] US 11078215 B2 discloses crystalline forms of Lorlatinib maleate namely hydrate Form 1 and hydrate Form 2.

[0012] US 11299500 B2 describes crystalline form of Lorlatinib free base Form 24.

[0013] There are various other patent applications which disclose various polymorphs of Lorlatinib.

[0014] It is widely accepted principle that new polymorphs of the same pharmaceutical active have different physicochemical properties such as stability, solubility, dissolution rate, crystal habit, densities. Any change in these properties may have an impact on the pharmaceutical properties of the drug.

[0015] The present invention relates to novel polymorphic forms of Lorlatinib which have improved physicochemical properties and further provides the processes for preparation thereof.

[0016] OBJECTIVES OF THE INVENTION

[0017] The primary objective of the present invention is to provide novel polymorphs of Lorlatinib.

[0018] The other objective of the present invention is to provide processes for the preparation of polymorphs of Lorlatinib.

[0019] Another objective of the present invention is to provide a pharmaceutical composition comprising novel polymorphs of Lorlatinib and pharmaceutically acceptable excipients.Yet another objective of the present invention is use of pharmaceutical composition for the treatment of non-small cell lung cancer.

[0020] SUMMARY OF THE INVENTION

[0021] In one aspect, present invention provides Lorlatinib polymorph Form Cl.

[0022] In another aspect, the present invention provides Lorlatinib polymorph Form Cl characterized by X-ray powder diffraction pattern (XRPD) as shown in Fig 1.

[0023] In another aspect, the present invention provides Lorlatinib polymorph Form Cl characterized by DSC thermogram as shown in Figure 2.

[0024] In further aspect, present invention provides Lorlatinib polymorph Form C2.

[0025] In another aspect, the present invention provides Lorlatinib polymorph Form C2 characterized by X-ray powder diffraction pattern (XRPD) prepared by example 3 as shown in Figure 3.

[0026] In an aspect, the the present invention provides Lorlatinib polymorph Form C2 characterized by X-ray powder diffraction pattern (XRPD) prepared by example 4 as shown in Figure 4.

[0027] In an aspect, the present invention provides Lorlatinib polymorph Form C2 characterized by DSC thermogram as shown in Figure 5.

[0028] In yet another aspect, the present invention provides Lorlatinib polymorph Form C2 characterized by TGA as shown in Figure 6.

[0029] In yet another aspect, the present invention provides Lorlatinib polymorph FormIn further aspect, the present invention provides Lorlatinib polymorph Form C3 characterized by X-ray powder diffraction pattern (XRPD) as shown in Figure?.

[0030] In an aspect, the present invention provides Lorlatinib polymorph Form C3 characterized by DSC as shown in Figure 8.

[0031] In yet another aspect, the present invention provides Lorlatinib polymorph Form C3 characterized by TGA as shown in Figure 9.

[0032] In yet another aspect, the present invention provides Lorlatinib polymorph Form C4.

[0033] In another embodiment, the present invention provides Lorlatinib polymorph Form C4 characterized by X-ray powder diffraction pattern (XRPD) as shown in Figure 10.

[0034] In an embodiment, the present invention provides Lorlatinib polymorph Form C4 characterized by DSC as shown in Figure 11.

[0035] In yet another aspect, the present invention provides processes for preparation of Lorlatinib polymorph Form Cl, Form C2, Form C3 and Form C4.

[0036] In another aspect, the present invention provides a pharmaceutical composition comprising novel polymorphs of Lorlatinib Form Cl, Form C2, Form C3 or Form C4 or may substantially consist of a combination of two or more of said forms along with

[0037] pharmaceutically acceptable excipients.

[0038] In yet another aspect, the present invention provides the use of pharmaceutical composition defined hereinabove for the treatment of non-small cell Lung cancer.

[0039] BRIEF DESCRIPTION OF THE FIGURESFigure 1 depicts X-ray powder diffraction spectrum (XRPD) of Lorlatinib Form Cl.

[0040] Figure 2 depicts DSC of Lorlatinib Form Cl as per example 1

[0041] Figure 3 depicts X-ray powder diffraction spectrum (XRPD) of Lorlatinib Form C2 as per example 3.

[0042] Figure 4 depicts X-ray powder diffraction spectrum (XRPD) of Lorlatinib Form C2 as per example 4.

[0043] Figure 5 depicts DSC of Lorlatinib Form C2 as per example 4

[0044] Figure 6 depicts TGA of Lorlatinib Form C2 as per example 4

[0045] Figure 7 depicts X-ray powder diffraction spectrum (XRPD) of Lorlatinib Form C3 as per example 6

[0046] Figure 8 depicts DSC of Lorlatinib Form C3 as per example 6

[0047] Figure 9 depicts TGA of Lorlatinib Form C3 as per example 6

[0048] Figure 10 depicts the X-ray powder diffraction spectrum (XRPD) of Lorlatinib Form C4 as per example 7

[0049] Figure 11 depicts the DSC of Lorlatinib Form C 4 as per example 7.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] Polymorphs are solid substances that possess different crystallographic modifications, each with its own specific crystal lattice framework. In the pharmaceutical industry, polymorphism plays a crucial role in drug development. The solid-state forms of the present invention have advantageous properties including solubility, dissolution rate, morphology, storage stability, flowability and bulk density.

[0052] In an embodiment, the present invention discloses Lorlatinib polymorph Form Cl. Form Cl is characterized by X-ray powder diffraction pattern (XRPD) having peaks at 9.35, 12.58, 13.38, and 22.94 ± 0.2°29. The X-ray diffraction of Form Cl is as depicted in Figure 1.In another embodiment, the present invention discloses Lorlatinib polymorph Form Cl characterized by DSC thermogram as shown in Figure 2. Accordingly, the DSC exhibits a broad endothermic peak at 201.29°C and an endothermic peak at 236.20°C and at 237.46°C.

[0053] In an embodiment, the present invention discloses Lorlatinib polymorph Form C2. This Form C2 may be characterized by X-ray powder diffraction pattern (XRPD) with peaks at 9.74, 12.73, 13.84, 15.74, and 24.86 ± 0.2°29. The X-ray diffraction of Form C2 prepared according to example 3 and example 4 is as depicted in Figure 3 and Figure 4.

[0054] In an embodiment, the present invention discloses Lorlatinib polymorph C2 characterized by DSC thermogram exhibiting endothermic peaks at 202.20°C and at 238.17°C as shown in Figure 5.

[0055] In another embodiment, the present invention discloses Lorlatinib polymorph C2 characterized by TGA exhibiting a weight loss of 0.524% as shown in Figure 6.

[0056] In yet another embodiment, the present invention provides Lorlatinib polymorph Form C3. This Form C3 may further be characterized by X-ray powder diffraction pattern (XRPD) with peaks at 8.87, 10.05, 17.26, 19.06, and 24.10 ± 0.2°29. The X-ray diffraction of Form C3 is as depicted in Figure 7.

[0057] In another embodiment, the present invention discloses Lorlatinib polymorph Form C3 characterized by DSC thermogram exhibiting endothermic peaks at 105.09°C and at 236.34°C as shown in Figure 8.

[0058] In yet another embodiment, the present invention discloses Lorlatinib polymorph Form C3 characterized by TGA exhibiting a weight loss of 19.260% as shown in Figure 9.In yet another embodiment, the present invention provides Lorlatinib polymorph Form C4. This Form C4 may further be characterized by X-ray powder diffraction pattern (XRPD) with peaks at about 6.5, 9.4, 10.6, 12.7, 13.7, 23.2 and 25.1 ± 0.2°29. The X-ray diffraction of Form C4 is as depicted in Figure 10; and Differential Scanning Calorimetry (DSC) with a peak temperature of about 201.10° C and 238.16° C. The Differential Scanning Calorimetry thermogram of Form C4 is as depicted in Figure 11.

[0059] In another embodiment, the present invention relates to the process for preparation of Lorlatinib polymorph Form Cl comprising:

[0060] a. suspending Lorlatinib in acetone at suitable temperature and stirring for suitable time; and

[0061] b. filtering and drying to obtain Lorlatinib Form C 1.

[0062] Suitable temperature used in step a. ranges from 0° C to 50° C, preferably 10° C to 40° C, more preferably 20° C to 30° C. The solid obtained was filtered and dried for a suitable period of time ranging from 10 minutes to 1 hour, preferably 15 to 50 minutes, more preferably 20 to 30 minutes.

[0063] The obtained Form Cl is an acetone solvate.

[0064] In an alternate embodiment, Lorlatinib polymorph Form Cl may be prepared by the process comprising:

[0065] a. suspending Lorlatinib in a first solvent at suitable temperature;

[0066] b. adding acetone to get a clear solution;

[0067] c. adding second suitable solvent to the clear solution obtained in step b. at a suitable temperature;

[0068] d. stirring the reaction mixture for suitable period of time; and

[0069] e. filtering and drying the obtained product to obtain Lorlatinib Form C 1.The first and second suitable solvent may be selected from but not limited to ethers (such as tetrahydrofuran, 2-methyl tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, isopropyl ether, anisole, diethyl ether); alcohols (such as methanol, ethanol, isopropanol, t-butanol), ketones (such as acetone, methyl isobutyl ketone, methyl ethyl ketone), alkyl nitriles (such as acetonitrile, propionitrile), hydrocarbons including halogenated hydrocarbons (such as cyclopentane, cyclohexane, methyl cyclohexane, heptane, toluene, xylene, dichloromethane), alkyl carbonate (such as dimethyl carbonate, diethyl carbonate) or mixture thereof.

[0070] In an embodiment, acetone may be added slowly to the reaction mass.

[0071] The suitable temperature at which steps a. to c. are carried out ranges from 0° to 45°C, preferably 10° to 35°C, more preferably 20° to 25°C.

[0072] The stirring of the solution in step c. may be carried out for about 1 to 5 hours, preferably 2 to 4 hours and more preferably for 2.5 to 3.5 hours.

[0073] The drying may be carried out by processes known in art.

[0074] In further embodiment, the present invention provides a process for the preparation of Lorlatinib Form C2 which comprises drying Lorlatinib Form Cl obtained by the present invention at suitable temperature and for suitable period of time.

[0075] The drying may be done in controlled and sequential manner.

[0076] In one aspect, Form Cl may first be dried at temperatures ranging from 20° C to 60° C, preferably 30° C to 50° C, more preferably 35° C to 45° C for 1 hour to 3 hours, preferably for 2 hours.The dried product may further be dried at a temperature ranging from 40° C to 80° C, preferably 50° C to 70° C, more preferably 60° C to 65° C for about 20 hours to 30 hours, preferably for about 15 hours to 25 hours.

[0077] In an alternate embodiment, Lorlatinib polymorph Form C2 may be prepared by the process which comprises steps of:

[0078] a. dissolving Lorlatinib in first solvent at a suitable temperature and stirring the solution for a suitable period of time;

[0079] b. cooling the resulted clear solution at a suitable temperature;

[0080] c. adding second solvent at a suitable temperature and stirring the solution for a suitable period of time; and

[0081] d. filtering and drying at a suitable temperature and suitable period of time to obtain Lorlatinib Form C2.

[0082] Step a. is carried out at a suitable temperature ranging from 40° C to 80° C, preferably 40° C to 60° C, more preferably 50° C to 60° C and stirred the solution for about 10 minutes to 1 hour, preferably for about 20 minutes to 40 minutes.

[0083] The first and second solvents may be selected from but not limited to acids (such as acetic acid, formic acid), esters (such as ethyl acetate, isopropyl acetate, n-propyl acetate), ethers (such as tetrahydrofuran, 2-methyl tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, isopropyl ether, anisole, diethyl ether), alcohols (such as methanol, ethanol, isopropanol, t-butanol), ketones (such as acetone, methyl isobutyl ketone, methyl ethyl ketone), alkyl nitriles (such as acetonitrile, propionitrile), hydrocarbons including halogenated hydrocarbons (such as cyclopentane, cyclohexane, methyl cyclohexane, n-heptane, n-hexane, toluene, xylene, dichloromethane), alkyl carbonate (such as dimethyl carbonate, diethyl carbonate), aprotic polar solvents (such as sulfolane, dimethyl sulfoxide, N-methyl pyrrolidone) or mixture thereof.

[0084] Step b. is carried out at a suitable temperature ranging from 15° C to 30° C, preferably 20° C to 30° C.Step c. is carried out at a suitable temperature ranging from 15° C to 30° C, preferably 20° C to 30° C and stirred the solution for about 10 hours to 24 hours, preferably for about 10 hours to 14 hours and about 20 hours to 25 hours.

[0085] In an aspect, in step d) Form C2 may first be dried at temperatures ranging from 30° C to 70° C, preferably 30° C to 50° C, more preferably 35° C to 45° C for about 1 hour to 95 hours, preferably for about 1 hours to 3 hours, preferably for about 30 hours to 40 hours and about 85 hours to 95 hours.

[0086] In another embodiment, process for the preparation of Lorlatinib polymorph C3 may be prepared by the process which comprises steps of:

[0087] a. dissolving Lorlatinib in n-propyl acetate at a suitable temperature and stirring the solution for a suitable period of time;

[0088] b. adding the resulting solution to a first solvent at a suitable temperature and stirring the solution for a suitable period of time; and

[0089] c. filtering the solution, washing the resulting solid with second solvent, and drying the solid to obtain Lorlatinib Form C3.

[0090] Step a. is carried out at a suitable temperature ranging from 40° C to 90° C, preferably 50° C to 80° C, more preferably 60° C to 70° C and stirred the solution for about 10 minutes to 1 hour, preferably for about 20 minutes to 40 minutes.

[0091] The first and second solvents may be selected from but not limited to acids (such as acetic acid, formic acid), esters (such as ethyl acetate, isopropyl acetate, n-propyl acetate), ethers (such as tetrahydrofuran, 2-methyl tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, isopropyl ether, anisole, diethyl ether), alcohols (such as methanol, ethanol, isopropanol, t-butanol), ketones (such as acetone, methyl isobutyl ketone, methyl ethyl ketone), alkyl nitriles (such as acetonitrile, propionitrile), hydrocarbons including halogenated hydrocarbons (such as cyclopentane, cyclohexane, methyl cyclohexane, n-heptane, n-hexane, toluene, xylene, dichloromethane), alkyl carbonate (such as dimethyl carbonate,diethyl carbonate), aprotic polar solvents (such as sulfolane, dimethyl sulfoxide, N-methyl pyrrolidone) or mixture thereof.

[0092] Step b. is carried out at a suitable temperature ranging from 5° C to 50° C, preferably 15° C to 40° C, more preferably 20° C to 30° C and stirred the solution for about 30 minutes to 5 hours, preferably for about 1 hour to 4 hours, more preferably 2 hours to 3 hours.

[0093] The product obtained in step c) may first be dried at a temperature ranging from 5° C to 60° C, preferably 15° C to 50° C, more preferably 20° C to 40° C for a period ranging from 30 minutes to 4 hours, preferably 1 hour to 3 hours. Subsequently the solid may further be dried at a temperature ranging from 30° C to 80° C, preferably 40° C to 70° C, more preferably 50° C to 60° C for a period ranging from 4.5 hours to 8.5 hours, preferably 5 hours to 7.5 hours, more preferably 5.5 hours to 6.5 hours.

[0094] The Form C3 may be n-propyl acetate solvate.

[0095] In another embodiment, the present invention relates to the process for preparation of Lorlatinib polymorph Form C4 which comprises steps:

[0096] a. heating Lorlatinib Form C2 obtained according to example 4 with heating ramp of 10°C / min using thermal treatment at a suitable temperature; and b. cooling the resulted solution at a suitable temperature to obtain Loraltinib Form C4.

[0097] Suitable temperature used in step a. ranges from 180° C to 200° C, preferably 190° C to 200° C.

[0098] Suitable temperature used in step b. ranges from 15° C to 30° C, preferably 20° C to 25° C.Lorlatinib used as a starting material can be obtained by any processes known in the art.

[0099] In an embodiment, Lorlatinib Form C2 obtained by the process of the present invention is stable and with high purity at various conditions during forced degradation study as shown in Example 8 below.

[0100] According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising polymorphic forms of Lorlatinib as described above, together with one or more pharmaceutically acceptable excipients. The Lorlatinib used in the preparation of pharmaceutical compositions may substantially consist of one of Forms Cl, C2, C3 or C4 described above, or may substantially consist of a combination of two or more of said forms.

[0101] According to yet another embodiment of the present invention there is provided use of polymorphic Forms of Lorlatinib as described above, in the preparation of a medicament useful in treating or preventing cancer, specifically lung cancer, more specifically Non-Small Cell Lung Cancer (NSCLC).

[0102] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

[0103] EXAMPLES

[0104] Example 1: Process for the preparation of Lorlatinib Form ClTo a suitable reaction vessel, Lorlatinib (5.0 g) was charged into cyclohexane (25ml) at 20-25°C to obtain a suspension. Acetone (50 ml) was added slowly to the suspension with stirring until a clear solution was formed. Subsequently, cyclohexane (100 ml) was added to the clear solution, and the resulting mixture was stirred for 3 hours. The resultant solid was isolated by filtration through a Pressure Nutsche Filter (PNF) under a nitrogen atmosphere. The filter cake was suck-dried under a nitrogen flow for 30 minutes to obtain Lorlatinib Form Cl. Yield: 2.5 gm

[0105] Example 2: Process for the preparation of Lorlatinib Form Cl

[0106] Lorlatinib (1.0 g) was suspended in acetone (3.0 ml) at a temperature of 20-25°C. The resulting suspension was stirred for a period of 3 hours at the same temperature. The resulted solid was then isolated by filtration using a Pressure Nutsche Filter (PNF) under a nitrogen atmosphere. The filter cake was subjected to suck-drying under a nitrogen flow for 30 minutes to obtain Lorlatinib Form Cl.

[0107] Yield: 0.8 gm

[0108] Example 3: Process for the preparation of Lorlatinib Form C2

[0109] Lorlatinib Form Cl obtained in example 1 was dried in a Vacuum Tray Dryer (VTD) at 40°C for 2 hours. The temperature was subsequently increased to 60-65°C, and drying was continued for 15-20 hours to afford Lorlatinib Form C2.

[0110] Yield: 2.3 gm

[0111] Example 4: Process for the preparation of Lorlatinib Form C2

[0112] Lorlatinib (250 g) was dissolved in acetone (1250 ml) at 50-55°C and stirred for 30 minutes. The resulting clear solution was cooled to 20-25°C, followed by the slow addition of n-heptane (6250 ml). After stirring for 20-24 hours, the resultingsolid was filtered and washed with n-heptane (750 ml). The wet material was dried in an agitated Nutsche Filter Dryer (ANFD) at 40°C for 2 hours, then at 60-65°C for 36 hours to obtain Lorlatinib Form C2.

[0113] Yield: 200 gm.

[0114] Example 5: Process for the preparation of Lorlatinib Form C2

[0115] Lorlatinib (5.0 g) was dissolved in acetone (25 ml) at 50-55 °C and stirred for 30 minutes to obtain a clear solution. The solution was cooled to 20-25 °C, followed by the slow addition of n-heptane (100 ml) at 20-25 °C. The resulting mixture was stirred for 10-12 hours. The resulting solid was filtered and washed with n-heptane (10 ml). The wet material was dried in a Vacuum Tray Dryer (VTD) at 40 °C for 2 hours, and subsequently at 60-65 °C for 93 hours to obtain Lorlatinib Form C2.

[0116] Yield: 4.2 gm.

[0117] Example 6: Process for the preparation of Lorlatinib Form C3

[0118] Lorlatinib (2.0 g) was dissolved in n-propyl acetate (6.0 ml) at 60-65°C and stirred for 30 minutes to obtain a clear solution. This solution was then added to n-heptane (60 ml) at 25-30°C and stirred for a period of 2-3 hours. The obtained solid was isolated by filtration and washed with n-heptane (5 ml). The resulting wet material was dried in a Vacuum Tray Dryer (VTD) at 40°C for 2 hours, and subsequently dried at 50-55°C for an additional 6 hours to obtain Lorlatinib Form C3.

[0119] Yield: 1.6 gm

[0120] Example 7: Process for the preparation of Lorlatinib Form C4

[0121] Lorlatinib Form C2 (50 mg), obtained according to the procedure in Example 4, was subjected to thermal treatment in a Thermogravimetric Analysis (TGA) instrument. The sample was heated to 195°C at a heating ramp of 10°C / min andsubsequently cooled to 25°C. The resultant material was analyzed by Powder X-ray Diffraction (PXRD), which confirmed the formation of Lorlatinib Form C4.

[0122] Example 8: Forced degradation study of Lorlatinib Form C2:

[0123]

[0124] Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims

Claims

We claim:

1. A Lorlatinib polymorph Form C2 characterized by (a) X-ray powder diffraction pattern comprising diffraction peaks at 29 angle values: 9.74, 12.73, 13.84, 15.74, and 24.86 ±0.2°. (b) DSC thermogram exhibiting endothermic peaks at 202.20°C and at 238.17°C; and (c) TGA exhibiting a weight loss of 0.524%.

2. A Lorlatinib polymorph Form Cl characterized by (a) X-ray powder diffraction pattern comprising diffraction peaks at 29 angle values: 9.35, 12.58, 13.38, and 22.94 ±0.2°; (b) DSC exhibiting a broad endothermic peak at 201.29°C and an endothermic peak at 236.20°C and at 237.46°C3. A Lorlatinib polymorph Form C3 characterized by (a) X-ray powder diffraction pattern comprising diffraction peaks at 29 angle values: 8.87, 10.05, 17.26, 19.06, and 24.10 ±0.2°; (b) DSC thermogram exhibiting endothermic peaks at 105.09°C and at 236.34°C; and (c) TGA exhibiting a weight loss of 19.260%.

4. A Lorlatinib polymorph Form C4 characterized by (a) X-ray powder diffraction pattern comprising diffraction peaks at 29 angle values: 6.5, 9.4, 10.6, 12.7, 13.7, 23.2 and 25.1 ±0.2°; and (b) DSC exhibiting endothermic peaks at 201.10° C and 238.16° C.

5. A process for preparing Lorlatinib polymorph Form Cl as claimed in claim 2, comprising:a) suspending Lorlatinib in acetone at suitable temperature and stirring for suitable time; andb) filtering and drying to obtain Lorlatinib Form C 1.

6. A process for preparing Lorlatinib polymorph Form Cl as claimed in claim 2, comprising:a) suspending Lorlatinib in a first solvent at suitable temperature;b) adding acetone to get a clear solution;c) adding second suitable solvent to the clear solution obtained in step b.at a suitable temperature;d) stirring the reaction mixture for suitable period of time; ande) filtering and drying the obtained product to obtain Lorlatinib Form Cl .

7. A process for preparing Lorlatinib polymorph Form C2 as claimed in claim 1, comprising:drying Lorlatinib Form Cl obtained in claim 5 or claim 6 at suitable temperature and for suitable period of time.

8. A process for preparing Lorlatinib polymorph Form C2 as claimed in claim 1, comprising:a) dissolving Lorlatinib in first solvent at a suitable temperature and stirring the solution for a suitable period of time;b) cooling the resulted clear solution at a suitable temperature;c) adding second solvent at a suitable temperature and stirring the solution for a suitable period of time; andd) filtering and drying at a suitable temperature and suitable period of time to obtain Lorlatinib Form C2.

9. A process for preparing Lorlatinib polymorph Form C3 as claimed in claim 3, comprising:a) dissolving Lorlatinib in n-propyl acetate at a suitable temperature and stirring the solution for a suitable period of time;b) adding the resulting solution to a first solvent at a suitable temperature and stirring the solution for a suitable period of time; andc) filtering the solution, washing the resulting solid with second solvent, and drying the solid to obtain Lorlatinib Form C3.

10. A process for preparing Lorlatinib polymorph Form C4 as claimed in claim 4 comprising:a) heating Lorlatinib Form C2 obtained in claim 7 or 8 with heating ramp of 10°C / min using thermal treatment at a suitable temperature; and b) cooling the resulted solution at a suitable temperature to obtain Loral tinib Form C4.

11. The process as claimed in claims 6 to 10 wherein the first and second solvents may be selected from but not limited to acids (such as acetic acid, formic acid), esters (such as ethyl acetate, isopropyl acetate, n-propyl acetate), ethers (such as tetrahydrofuran, 2-methyl tetrahydrofuran, t-butyl methyl ether, cyclopentyl methyl ether, isopropyl ether, anisole, diethyl ether), alcohols (such as methanol, ethanol, isopropanol, t-butanol), ketones (such as acetone, methyl isobutyl ketone, methyl ethyl ketone), alkyl nitriles (such as acetonitrile, propionitrile), hydrocarbons including halogenated hydrocarbons (such as cyclopentane, cyclohexane, methyl cyclohexane, n-heptane, n-hexane, toluene, xylene, dichloromethane), alkyl carbonate (such as dimethyl carbonate, diethyl carbonate), aprotic polar solvents (such as sulfolane, dimethyl sulfoxide, N-methyl pyrrolidone) or mixture thereof.

12. The process as claimed in claim 7 or 8, wherein the drying is carried out in controlled and sequential manner.

13. The process as claimed in claim 7 and 12, wherein Form Cl is first dried at temperature ranging from 20° C to 60° C, for 1 hour to 3 hours, followed by drying at a temperature ranging from 40° C to 80° C, for 20 hours to 30 hours to obtain Lorlatinib Form C2.

14. A pharmaceutical composition comprising the Lorlatinib Form Cl or Form C2 or Form C3 or Form C4 or mixtures thereof as claimed in any one of the preceding claims 1 to 13 together with acceptable excipients.

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