DESC:
FIELD OF THE INVENTION
The present invention relates to a novel solid state form of Apalutamide and the process for its preparation.

BACKGROUND OF THE INVENTION
Apalutamide is an androgen receptor inhibitor that has been approved in the USA and the EU for the treatment of prostate cancer. This drug substance is prescribed for adult men who have been diagnosed with non-metastatic castration-resistant prostate cancer (nmCRPC) or with metastatic hormone-sensitive prostate cancer. Its chemical name is (4-[7-(6-Cyano-5-trifluoromethyl pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide) and is shown below in the structure of formula I –

Formula I
Apalutamide was developed by scientists at the University of California and is reported in various publications such as Cancer Res. 2012, 72(6): 1494–1503, J Med Chem. 2010, 53(7): 2779–2796 and US 8,445,507 B2. In contrast to the other drugs that were approved prior to Apalutamide, i.e. the first generation drugs for the treatment of prostate cancer, Apalutamide is a selective antagonist of the androgen receptor. Continued interest in the molecule has led to other publications that report its synthesis, such as US 11,040,953 B2, US 9,688,655 B2 and US 10,513,504 B2; as well as its polymorphic modifications, such as in WO2013/184681, US 11,149,017 B2, US 11,066,384 B2, IN201841002315 and WO2020/049598.

While Apalutamide is now available in the form of a tablet dosage form, during initial development, the drug substance was formulated as a liquid emulsion in soft gel capsules for clinical studies. The approved dosage form is also of a higher strength, viz. 60 mg, than that originally used in the form of the liquid emulsion. Furthermore, since its original regulatory approval, the drug has been reformulated to a still higher strength (240mg). It is thus a constant endeavour of the research scientist to provide a drug product that has a better pharmacokinetic profile than what is known. Keeping that precept at the forefront, the present inventors have worked upon another factor that impacts apalutamide's pharmacokinetic profile – its aqueous solubility. For the drugs that are administered orally, the aqueous solubility of the drug substance is the primary factor that affects the bioavailability of the drug. The CHMP assessment report of the European Medicines Agency for Apalutamide discloses that its aqueous solubility is low, viz. 0.001 g/100 mL.

One of the techniques employed to improve the solubility of a drug substance is to convert it to a co-crystal. Co-crystals are a solid state form wherein more than one compound constitutes the crystal lattice in discrete stoichiometric ratios. The compounds that form the lattice are, usually, neutral species and are held together by non-ionic interactions. Each such compound is called a coformer.

In the present invention, the novel co-crystal of Apalutamide with 4-acetamidophenol has been created.

SUMMARY
The present invention relates to a co-crystal of Apalutamide with 4-acetamidophenol. The co-crystal is prepared by grinding the two compounds together in a solvent, dissolving them in the solvent and cooling the solution. It is characterized by powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry and thermogravimetry.

BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 shows the pXRD of Apalutamide : 4-acetamidophenol co-crystal.
Fig. 2 shows the DSC of Apalutamide : 4-acetamidophenol co-crystal.
Fig. 3 shows the TGA of Apalutamide : 4-acetamidophenol co-crystal.
Fig. 4 shows the IR pattern of Apalutamide : 4-acetamidophenol co-crystal.

DETAILED DESCRIPTION
In one aspect of the invention the co-crystal of Apalutamide with 4-acetamidophenol (paracetamol) is provided. In one embodiment of the invention, the co-crystal of Apalutamide with 4-acetamidophenol is characterized by a pXRD pattern substantially as shown in Fig. 1. Representative peaks of the pXRD pattern of Fig. 1 are 7.53, 10.53, 10.77, 11.08, 12.25, 14.50, 15.08, 15.40, 16.73, 17.03, 20.78, 21.64, 22.26, 22.70, 23.73, 24.31, 27.68, 36.84, 38.31 ±0.2 degrees 2 theta.
In a second embodiment, the co-crystal of Apalutamide with 4-acetamidophenol is characterized by a pXRD pattern having peaks at 7.53, 12.25, 14.50 and 22.70 ±0.2 degrees 2 theta.

In a third embodiment, the co-crystal of Apalutamide with 4-acetamidophenol is characterized by DSC substantially as shown in Fig. 2. The DSC thermogram has a peak onset at about 152?C and an endothermic peak at about 159?C.

In a fourth embodiment, the co-crystal of Apalutamide with 4-acetamidophenol is characterized by a TGA substantially as shown in Fig. 3.

In a fifth embodiment, the co-crystal of Apalutamide with 4-acetamidophenol is characterized by an IR pattern substantially as shown in Fig. 4.

In another aspect, a process to prepare the co-crystal of Apalutamide with 4-acetamidophenol is provided. Apalutamide and 4-acetamidophenol that may be used as the input for the process of the invention may be obtained by any process including the process described in the prior art. The co-crystal can be prepared by dissolving the two compounds (i.e., Apalutamide and 4-acetamidophenol) in a suitable solvent and cooling the solution to allow the crystals to form. Suitable solvents that may be used may be selected from the group comprising of alcohols, ketones, esters, ethers, hydrocarbons, chlorinated hydrocarbons, water, nitriles and mixtures thereof in a suitable proportion. The preferred solvent is ethyl acetate.

The process for the preparation of the co-crystal may be carried out at a temperature between room temperature and reflux temperature; preferably the solution may be heated at 40-80°C until a clear solution is obtained. The solution obtained above may be optionally filtered to remove any insoluble particles. The solution may optionally be treated with carbon, Hyflo or any other suitable material to remove colour and/or to clarify the solution. The solution can be allowed to cool slowly and the crystals may be isolated using suitable techniques such as filtration, evaporation, distillation, decantation, vacuum drying, centrifugation and the like. After separation, the solid may optionally be washed with a suitable solvent. The isolated crystalline form may be dried at suitable temperature, preferably at 30-80°C for a period of about 1 hour to about 12 hours. Drying may be suitably carried out in an equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like for the required time to obtain a product with desired purity.

In an another aspect of the invention, the co-crystal of Apalutamide with 4-acetamidophenol prepared according to the processes of the application can be substantially pure, having a chemical purity greater than about 99% or greater than about 99.5% by weight when measured by high performance liquid chromatography.

In yet another aspect, a pharmaceutical composition comprising the co-crystal of Apalutamide : 4-acetamidophenol along with one or more pharmaceutically acceptable excipients is provided. The pharmaceutical composition may be safely administered orally or non-orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual.

In yet another aspect, the use of the co-crystal of Apalutamide with 4-acetamidophenol to prepare a medicament for the treatment of prostate cancer is provided.

As used herein, the term “about” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” means within 25%,20%,15%,10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

EXAMPLES
Following examples are set forth to aid in the understanding of the invention, and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combination thereof, are envisioned as part of the invention.

Example 1 - Preparation of co-crystal of Apalutamide with 4-acetamidophenol
Apalutamide (2.0 g) was taken in a mortar and 4-acetamidophenol (0.6333 g) was added to it. Ethyl acetate (2.0 mL) was added to it dropwise. The material was ground well at room temperature and then transferred to a conical flask. Ethyl acetate (16.0 mL) was added again. The solution was warmed to 70?C in a water bath, until the solid dissolved. The clear solution was set aside and allowed to cool naturally to room temperature. After cooling overnight, solid crystals were isolated and dried to obtain the title compound (yield: 2.27g) and further characterized by pXRD (Fig. 1), DSC (Fig. 2), TGA (Fig. 3), IR (Fig. 4).
,CLAIMS:
1. Apalutamide 4-acetamidophenol co-crystal.

2. The Apalutamide 4-acetamidophenol co-crystal according to claim 1, characterized by pXRD pattern substantially as shown in Fig. 1.

3. The Apalutamide 4-acetamidophenol co-crystal according to claim 1, further characterized by pXRD peaks at 7.53, 12.25, 14.50 and 22.70 ±0.2 degrees 2 theta.

4. The Apalutamide 4-acetamidophenol co-crystal according to claim 1 characterized by pXRD peaks at 7.53, 10.53, 10.77, 11.08, 12.25, 14.50, 15.08, 15.40, 16.73, 17.03, 20.78, 21.64, 22.26, 22.70, 23.73, 24.31, 27.68, 36.84, 38.31 ±0.2 degrees 2 theta.

5. The Apalutamide 4-acetamidophenol co-crystal according to claim 1, further characterized by DSC substantially as shown in Fig. 2.

6. The Apalutamide 4-acetamidophenol co-crystal according to claim 1, further characterized by DSC endothermic peak at about 159?C.

7. The Apalutamide 4-acetamidophenol co-crystal according to claim 1, further characterized by TGA substantially as shown in Fig. 3.

8. The Apalutamide 4-acetamidophenol co-crystal according to claim 1, further characterized by IR spectrum substantially as shown in Fig. 4.

9. A process for preparing the Apalutamide 4-acetamidophenol co-crystal according to claim 1, the process comprising the steps of
a. grinding Apalutamide and 4-acetamidophenol,
b. dissolving the ground substance comprising Apalutamide and 4-acetamidophenol in ethyl acetate,
c. cooling the solution,
d. isolating the crystals.

10. Use of an Apalutamide 4-acetamidophenol co-crystal according to claim 1 for the preparation of a medicament to treat prostate cancer.