Technics! field of invention:

The present invention relates to the novel crystalline and amorphous forms of Olaparib, their methods of preparation and pharmaceutical compositions comprising said crystalline and amorphous forms.

Background of the invention;

Olaparib is chemically known as 4-[3 -{4-ey copropane butaxycarbonylpiperizine-1 - carbonyl)-4-fluorobenzyl]-2M-phthaIazi.n- 1 -ketone, can be used to provide a pofy-ADP- ribose polymerase (PARP) inhibitor action. This effect can be used for the treatment of cancer, such as breast cancer or ovarian cancer, which can be particularly effective in the treatment of the cells in the homologous recombination (HR) dependent DMA double- stranded break (DSB) repair pathway. BRCA I (N .007295.) and BRCA 2 (NM_000059) hereditary breast/ovarian cancer genes are just 2 out of many proteins in the HR dependent DNA DSB repair pathway. Olaparib has the following chemical structure:

and is disclosed and exemplified in PCT Publication No. WO 2004/080976, (compound

PCT Publication No. WO2G08/047082, which is hereby incorporated by reference, discloses crystalline form A and process for the preparation thereof. PCX Publication No. WO2009 050469, which is hereby incorporated by reference, discloses crystalline form L and process for the preparation thereof.

POT Publication No. WO2010/04105 1 describes Olaparib in a solid dispersion with a matrix polymer.

Polymorphism is the ability of a compound to exist in two or more different crystalline phases thai differ in arrangement of the molecules in crystal lattice. Although polymorphs have the same chemical composition, they differ in packing and geometrical arrangement. and exhibit different physical properties such as melting point. X-ray diffraction patterns, density, stability, and solubility.

Extensive study is carried out in pharmaceutical industry lor development of different polymorphs of various drug substances, to obtain suitable polymorphs that possess improved performance characteristics such as aqueous solubility, improved bioavailability, chemical stability, shelf life etc.

Therefore, there is a need of having alternative polymorphic forms of Olaparib and processes for the preparation thereof.

Description of drawings:

Figure 1 1 Illustrates X-ray powder diffraction pattern of crystalline Form M of Olaparib.

Figure 2: Differential Scanning Calorimetry thermogram of crystalline Form M of

Olaparib. Figure 3 : Therm ogravi etric analysis curve of crystalline Form M of Olaparib.

Figure 4: Ill ustrates X-ray powder diffraction pattern of amorphous Form of Olaparib. Figure 5; Differential Scanning Calorimetry thermogram of amorphous Form of Olaparib. Figure 6: Thermogravi metric analysis curve of amorphous Form of Olaparib. Summary of the. invention:

In one aspect, the present invention provides a stable crystalline Form M of Olaparib with XPRD as shown herein in Figure 1.

In another aspect, the invention provides a process for the preparation of crystalline Form of Olaparib.

In another aspect, the invention provides a pharmaceutical composition comprising said stable crystalline Form M and at least one pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides an amorphous form of Olaparib, In another aspect, the invention provides a process for the preparation of an amorphous form of Olaparib.

in another aspect, the invention provides a pharmaceutical composition comprising said amorphous form and at least one pharmaceutically acceptable excipient or carrier.

Detail Description of the Invention: The term "excipient" or "pharmaceutically acceptable excipient ^* ' means a component of a pharmaceutical product that is not an active ingredient and includes but not limited to fillet; diluent, disintegrants. glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

The term "stable" herein means crystall ine form that substantially does not convert to any other solid form. in one embodiment of the invention, the present invention provides a stable crystalline Form M of Olaparib. in another embodiment, the present invention provides a crystalline Form M of Olaparib, which is characterized by XRPD (X-ray powder dtffractogram) which comprises of peaks expressed as 2Θ at J 0.25, 13.27, 13.97, 17,45, 20.68, 22.06, 23.3 1. 25.61 , 28.99 ± 0.2 degrees. The XRPD of crystalline Form of Oiapan ^' b is depicted in figure 1.

In another embodiment, the present invention provides a process for the preparation of a crystalline Form M of Olaparib. which comprises the steps of: i) stirring a mixture Olaparib and n-heptane solvent; ii) isolating the crystalline Form M of O!aparib.

In one embodiment, step ( i) is carried our at a temperature of about 0 to about 70°C.

The isolation of crystalline Olaparib of step (ii) could be done by conventional techniques known to a person skilled in the art such as fi ltration, centrifugati n etc.

In another embodiment, the present invention provides a pharmaceutical composition comprising Form M of crystalline Olaparib with pharmaceutically acceptable exeipients. The Form M. of crystalline Olaparib can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dr granulation, wet granulation, melt granulation, direct compression, double com ression, extrusion spheromzatton, layering and the like. The composition or formulation may be coated or uncoated. Coati ng of compositions such as tablets and capiets is well known in the art.

Although for many pharmaceutical compounds, oral administration in the form of a tablet or capsule is preferred, some patients, for example elderly and paedjatric patients, may have difficulties in swallowing such formulations. Therefore, liquid formulations such as oral solutions may offer a suitable alternative, avoiding the need of swallowing tablets or capsules. An oral solution further provides the possibility of a more flexible closing regimen. In order to limit the volume of an oral solution it is necessary to have a high concentration of the active ingredient in the solution, which again requires a high, solubility of the active ingredient. Hence the superior solubility of Form M of crystalline Olaparib of 'the present invention makes this particular solid state form especially suitable for the preparation of liquid pharmaceutical formulations such as oral solutions.

Pharmaceutically acceptable excipients may be utilized as required for conversion of the

Form M of crystalline Olaparib into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives thai are commonly used in solid pharmaceutical dosage form preparations.

The present invention includes crystalline Form M of Olaparib may be used in the preparation of a medicament for the treatment of cancer which is deficient in Homologous Recombination (HR) dependent DMA DSB repair activity, or in the treatment of a patient of a cancer which is deficient in HR dependent DNA DSB repair activity, comprising administering to said patient a therapeuticaiiy-effective amount of the compound. in another embodiment, the present invention provides an amorphous form of Olaparib. The XPRD of amorphous form of Olaparib is depicted in fig 4.

In another embodiment, the invention provides a process for preparation of an amorphous form of Olaparib comprising, the steps of:

a) providing a solution of Olaparib in one or more solvents; and b) obtaining the amorphous form of Oiaparib by removal of solvent ^' s). The solvent employed in step a) is selected from the group consisting of water, ^' methanol, ethanol, isopropanol, 2-propanol, 1 -butanoi, t-batyl alcohol, 1 - pentano!, 2-pentanol, amyl alcohol ethylene glycol, glycerol, acetone, butanone, 2-peiitanone, 3-pentartone, methyl butyl ketone, methyl isobuiyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobuiyl acetate, toluene, xylene, methylene dichioride, ethylene dichioride, chlorobenzene, acetonitrile, diethyl ether, diisoprop l ether, t-butyl methyl ether, dibut l ether, ietrahydrofuran, 1 ,4-dioxane. 2-methoxyethanoi. N, N- dimethylformamide, N,N-di methy {acetamide, N-niethylpyrroiidone, pyridine, dimethy Isul foxide, sulfoiane, formamide, acetamide, propanamtde, pyridine, formic acid, acetic acid, propionic acid or mixtures of at least two thereof;

Step b) involves isolation of an amorphous form of Olaparib from the solution of step a). The- isolation may be affected by removing the solvent! s). Suitable techniques which may be used for the removal of solvent include using a rotational distillation device such as a rotary evaporator {e.g., Buchi Rotavapor), spray drying, agitated thin film drying ("ATFD"). freeze drying (iyophihzation), and the like or any other suitable technique.

Alternatively, isolation can be effected by addition of suitable anti-solvent to the solution obtain in step a), optionally by concentrating the solution obtained in step a). Suitable anti-solvents that may be used can be selected from one or more of hydrocarbons like hexanes, n-heptane, n- pen lane, cyelohexane, merh !cyciohexane and the like: aromatic hydrocarbons like toluene, xylene, ethylbenzene and the like: ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, i ,4-dioxane. 2- rnethoxyethonol and the like or water.

!n another embodiment, the present invention provides a pharmaceutical composition comprising an amorphous form of Olaparib. The amorphous form of Olaparib can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc.

The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. The composition or formulation may be coated or imcoated. Coating of compositions such as tablets and caplets is well known in the art.

Although for many pharmaceutical compounds oral administration in the form of a tablet or capsule is preferred, some patients, for example elderly and pediatric patients, may- have difficulties in swallowing such formulations. Therefore, liquid formulations such as oral solutions may offer a suitable alternative, avoiding the need of swallowing tablets or 2017/051407

7

capsules. A n oral solution further provides the possibility of a more flexible dosing regimen. In order to limit the volume of an oral solution it is necessary to have a high concentration of the active ingredient in the solution, which again requires a hig solubility of the active ingredient. Hence the superior solubility of the amorphous form of Olapavib of the present invention makes this particular solid state form especially suitable for the preparanon of liquid pharmaceutical formulations such as oral solutions.

Pharmaceutically acceptable excipients may be utilized as required for conversion of the amorphous form of Olaparib into the final pharmaceutical dosage forms and include, for example, any one or more of diluents, binders, stabilize rs, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in solid pharmaceutical dosage form preparations.

The present invention provides the use of a crystalline Form M of Olaparib in the preparation of a medicament for the treatment of cancer which, is deficient in Homologous Recombination (HR) dependent DNA DSB repair activity, or in the treatment of a patient of a cancer which is deficient in HR dependent DMA DSB repair activity, comprising administering to said patient a therapeutically effective amount of the com ound.

The diluents, binders, bulking agents, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in sol id pharmaceutical dosage form preparations Includes Diluents :

Various useful fillers or diluents include but are not limited to starches, lactose, mannitoi (Pea.rlitoi ^fM SD200 ), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include but are not limited to lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowkic ^{i !} . Pharinatose ^f¾i and others. Different, starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and starch J 500, starch 1500 LM grade {low moisture content grade) from Coloreon, fully pregelaiinized starch and others. Different cellulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include bui are not limited to CEOLUS™ G801 . A vice!™ PHI 01 , PHI 02, PH301 , PH302 and PH-F20, PH I 12 micToerysta!lme cellulose 1 14, and microcrystalJine cellulose i 12. Other useful diluents include but are not limited to caimellose, sugar alcohols such as mannitol (Pearlitol ^{5 M} SD200). sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and trtbasic calcium phosphate.

Binders:

Various useful binders include but are not limited to hydroxypropylceUuloses. also called HPC { lucel™ LF. lucel EXF) and useful in various grades, hydroxy propyl roethylce!luioses. also called hypromei loses or HPMC (Methocel™) and useful in. various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP- 29, PVP- 30, and PVP-K90). Piasdone™ S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (Carbopol ^{! M} ), methyleeliuioses, polymethacrylates, and starches.

Bulking agents:

Bulking agents are ingredients which may provide bulk to a pharmaceutical composition. Various useful binders include but are not lim ited to PEG s, mannitol, trehalose, lactose, sucrose, polyvinyl pyrrol idone, sucrose, glycine, cyclodexirins, dextran and derivatives and mixtures thereof.

Disintegrants:

Various useful disintegrants include but are not limited to carme ^' ilose calcium, carboxymethylstarch sodium, croscarmellose sodium:, crospovidones, examples of commercially available crospovidone products including but not limited to crossl inked povidone, ollidon™ CL, Poiypiasdone™ XL, XI- 10, and INF- 10 and low-substituted hydroxypropyicelluioses. Examples of low-substituted ^' hydroxypropyicelluloses incl ude but are not limited to low-substituted hydroxypropyiceikiiose LH1 i , 1..H2 L LH31 , LH22, LH32, LH.20, LH3G, LH32 and LH33. Other useful disintegrants include .sodium starch giycolate, colloidal silicon dioxide, and starches. Stabilizers:

Various useful stabilizers include basic inorganic salts, such as but not limited to basic, inorganic salts of sodium, potassium, magnesium and calcium. Examples of basic inorganic salts of sodium are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples, of basic, inorganic salts of magnesium are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasificate aluni _. inate, magnesium silicate, magnesium alaminate, synthetic hydrotalcite [M _f tAk(OH)i*.C0 ₃ .4H20], aluminum hydroxide-magnesium [2.5MgO.Al _∑ <¾.xH ₂ 0}. and the like. Examples of basic inorganic salts of calcium include precipitated calcium carbonate, calcium hydroxide, and the like.

Surface-Active Agents:

Useful surface-active agents include non-tonic, ca iontc and anionic surface-active agents. Useful non-ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPAN™) and polyhydroxyethyienicaSl treated sorbitan esters (TWEEN ^£M ), aliphatic alcohols and PEG ethers, phenol and PEG ethers. Useful eationk surface-active agents include quaternary ammonium salts (e.g. cetyltrsmethylammoniura bromide) and amine salts (e.g. octadecyiamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearaie, and calcium stearate, triethenolamine stearate. sodium iauryl sulphate, sodium dioctylsuiphosuccinate, and sodium dodeeylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacyiphosphaiidyl glycerols, diaceylphosphatidyl cholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as for example soybean lecithin and egg yo!k.

Lubricants:

An effective amount of any pharmaceutically acceptable tabieting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, ca nauba wax, calcium stearate sodium, sodium or magnesium iauryl sulfate, calcium soaps, zinc srearate, polyoxyethylsoe monostearates. calcium .silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and combinations thereof. Glidants:

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variations can be used. Useful glidants include but are not limited to silicone dioxide, talc and combinations thereof. Coloring Agents;

Coloring agents can be used to color code the compositions, for example., to indicate the type and dosage of the therapeutic, agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combinations thereof, and the. like.

Useful additives for coatings include but are not limited to plasticizers. antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, ant ^' tfoam agents, and polishing agents.

P!asticizers:

Various useful plasticizers include but are not limited to substances such as castor oil diacetyiated monoglycerides, dibutyl. sehacate. diethyl phthaiate, glycerin, polyethylene glycol, propylene glycol, triacetin, a trtethyi citrate. Also, mixtures of plastic izers may be utilized. The type of plasticizer depends upon the type of coating agent. An opacifier like ti fianium dioxide may also be present, typically in an amount ranging from about 10% to about 20% based, on the total weight of the coa ting.

Examples: Example 1: Preparation of amorphous form ^' of Olaparib:

10.0 gm of O!aparib and 500 ml of methanol were taken in to round bottom ilask at 25- 30°C. The reaction mixture was heated to 70*C on water bath and filtered. The methanol solvent was evaporated over rotavapor. The resulting solid was dried in oven under a vacuum to get 8.3 gm of desired compound.

Example 2 :

Preparation of crystalline Form of Olaparib;

9.0 gm of amorphous Olaparib and 270 ml of n-heptane were taken in to round bottom flask at 25-30 . Reaction mixture was stirred at 25-30°C for 20 hours, the resulting solid was filtered and was dried in oven under a vacuum to get 8.0 gin of desired compound.

Example 3:

Preparation of hydrated form of Olaparib:

10.0 gm of Olaparib was dissolved in 50 ml of DMF at S0-60°C and cooled to room temperature. 500 mi of water was taken in to round bottom flask at 25-30°C and stirred, DMF sofution of Olaparib was added to above water dropwise at 25*30°C and stirred for 2 hoars. The resulting solid was filtered and dried in oven under vacuum to get 9.2 gm of desired compound.

Example 4:

Preparation of crystalline Form M of Olaparib: 9.0 gm of Olaparib hydrate and 270 ml of n-heptane were lakeQ in to round bottom flask at 25-30°C. Reaction mixt ure was stirred and heated at 55-60°C for 25 hours. The resulting solid was filtered and dried in oven under vacuum to get 8.8 gm of desired compound.