Background of the Invention
Pharmaceutical actives used to manufacture various dosage forms like tablets, capsules, suspensions, injections etc can be prepared in a variety of different forms. These APIs (active pharmaceutical ingredients) can be prepared to have a (i) variety of different chemical forms including chemical derivatives or salts or (ii) different physical forms. The APIs may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of an API, it is possible to vary the physical properties thereof. Pharmaceutical polymorphs have different solubilities from one another and can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Therefore changing the crystalline state of an API is one of many ways to modulate the physical properties thereof.
It would be advantageous to have new forms of these APIs with improved properties like increased aqueous solubility and stability. This is also applicable for the antidepressant compound, Agomelatine, developed by Servier.
Agomelatine is a melatonin receptor agonist sold as Valdoxan®. Agomelatine has the chemical name N[2-(7-methoxy-l-naphthyl)ethyl] acetamide and has the following structure.
Agomelatine, its preparation and its use in therapeutics have been described in European patents EP 0447285 and EP 1564202.

U.S Pat. No.s 7,250,531 and 7,498,465 to Souvie, et al describe crystalline form II of Agomelatine, a process for its preparation and pharmaceutical compositions containing it.
U.S Pat. No.s 7,635,721 and 7,939,566 to Coquerel, et al describe crystalline form III of Agomelatine.
U.S Pat. No.s 7,645,905 and 7,910,625 to Coquerel, et al describe crystalline form IV of Agomelatine.
U.S Pat. No. 7,358, 395 to Coquerel, et al describe crystalline form V of Agomelatine.
PCT Int. Appl. WO 2012/130837 to Stefan et al., disclose composition comprising non-crystalline form of Agomelatine.
PCT Int. Appl. WO 2015/013903 to Shan Hanbin et al., describe p-toluenesulfonic acid co-crystals of Agomelatine.
The present invention relates to stable novel co-crystal forms of Agomelatine with improved solubility, making it favourable for use in the manufacture of pharmaceutical formulations.
Summary of the invention
The invention provides stable novel co-crystal forms of Agomelatine and pharmaceutical formulations comprising the novel co-crystal forms.
The invention also relates to a process of manufacture of Agomelatine co-crystals.
The invention further relates to Adipic acid co-crystal of Agomelatine and process of preparation thereof and pharmaceutical formulations comprising the same.

The invention also relates to Saccharin co-crystal of Agomelatine and process of preparation thereof and pharmaceutical formulations comprising the same.
Brief description of the drawings
Fig 1: Depicts powder X-ray diffraction pattern ("Powder XRD" or "PXRD") of Adipic acid co-crystal of Agomelatine obtained in example 1.
Fig 2: Depicts powder X-ray diffraction pattern ("Powder XRD" or "PXRD") of Saccharin co-crystal of Agomelatine obtained in example 2.
Fig 3: Depicts powder X-ray diffraction pattern ("Powder XRD" or "PXRD") of Saccharin co-crystal of Agomelatine obtained in example 3.
Fig 4: Depicts a DSC (Differential Scanning Calorimetry) thermogram of Adipic acid co-crystal of Agomelatine obtained in example 1.
Fig 5: Depicts a DSC (Differential Scanning Calorimetry) thermogram of Saccharin co-crystal of Agomelatine obtained in example 2.
Fig 6: Depicts Infrared spectrum of Adipic acid co-crystal of Agomelatine obtained in example 1.
Fig 7: Depicts Infrared spectrum of Saccharin co-crystal of Agomelatine obtained in example 2.
Detailed description of the invention
The present invention is related to novel co-crystal forms of Agomelatine, process of preparation and solid oral pharmaceutical formulations containing them.
In one embodiment of the co-crystal according to the invention, the co-crystal former is selected from Adipic acid and Saccharin.
"Co-crystal" as used herein is defined as a crystalline material comprising two or more compounds of which at least two are held together, wherein at least one of the compounds is a co-crystal former.

"Co-crystal-former" as used herein is defined as a component with which Agomelatine is able to form co-crystals. The co-crystal former is part of the crystal lattice.
The "intrinsic dissolution rate" is defined as the dissolution rate of pure substances under the condition of constant surface area.
Agomelatine is practically insoluble in purified water (< 0.1 mg/mL) but freely soluble (> 100 mg/mL) in various organic solvents (96% ethanol, methanol, methylene chloride). Solubility in water and aqueous media is a desired characteristic of APIs to ensure physiological absorption and bioavailability. Intrinsic dissolution rate is often used as a powerful tool for the evaluation of solubility.
The inventors of the present invention have found that the novel co-crystals of Agomelatine produced according to the invention have significantly higher solubility than Agomelatine API. The inventors prepared the co-crystals of Agomelatine using Adipic acid or Saccharin and determined solubility by measuring the intrinsic dissolution rate.
Experiments were carried out to compare the intrinsic dissolution rate (DDR) of Adipic acid and Saccharin co-crystals of Agomelatine with Agomelatine API using dissolution apparatus (rotary disc method) in various dissolution media at 37°C and 100 RPM (rotations per minute). The results are tabulated in table 1.

Agomelatine co-crystal forms can be characterized by one or more analytical techniques, like X-ray powder diffraction pattern (XRPD), infrared absorption spectra and differential scanning calorimetry (DSC) curves.
Thus one aspect of the invention relates to Adipic acid co-crystal of Agomelatine, comprising of Agomelatine in the form of co-crystal with Adipic acid. The molar ratio of Agomelatine to Adipic acid is preferably 1:1, which resulted in a stable co-crystal form of Agomelatine.
The Adipic acid co-crystal of Agomelatine can be characterized by any one or all of the following characteristics:
(i) an X- ray powder diffraction pattern at 20 values of 21.5, 19.6, 19.8, 25.7 ± 0.2
degrees 29. (ii) an infrared absorption spectrum comprising infrared absorption bands at: 3072,
1625 cm"1. (iii)an endothermic trace comprising an endothermic peak at about 87.7°C in a DSC (Differential Scanning Calorimetry) thermogram
Another aspect of the invention relates to Saccharin co-crystal of Agomelatine, comprising of Agomelatine in the form of co-crystal with Saccharin. The molar ratio of Agomelatine to Saccharin is preferably 1:1, which resulted in a stable co-crystal form of Agomelatine.
The Saccharin co-crystal of Agomelatine can be characterized by any one or all of the following characteristics:

(i) an X- ray powder diffraction pattern at 29 values of 25.1, 16.0, 19.1 ± 0.2
degrees 29. (ii) an infrared absorption spectrum comprising infrared absorption bands at: 3240,
1717 cm"1. (iii)an endothermic trace comprising an endothermic peak at about 91.0°C in a DSC (Differential Scanning Calorimetry) thermogram
Yet another aspect of invention, relates to process of preparing the said co-crystal of Agomelatine. The process comprises:
(i) Blending and co-sifting Agomelatine with Saccharin/Adipic acid in suitable
proportions (ii) Dry grinding the co-sifted material using Ball Mill/Hammer Mill/High Shear
Granulator or any suitable equipment (iii)Sifting and collecting the ground material.
Yet another aspect of invention, relates to process of preparing the said co-crystal of Agomelatine. The process comprises:
(i) Dry mixing Agomelatine and co-crystal-former in suitable proportions (ii) Co-melting the above dry mixed material (iii)Cooling the above melted co-crystal material
(iv)Addition of solvent to step (iii), followed by evaporating the solvent and collecting the material.
Yet another aspect of the invention relates to pharmaceutical formulation of Agomelatine tablets comprising of Adipic acid co-crystal of Agomelatine and other pharmaceutically acceptable excipients.
Yet another aspect of the invention relates to pharmaceutical formulation of Agomelatine tablets comprising of Saccharin co-crystal of Agomelatine and other pharmaceutically acceptable excipients.

Agomelatine tablet formulations prepared according to the invention can be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulations may be presented as coated or uncoated tablet. Pharmaceutically acceptable excipients used in the tablet formulations of Agomelatine include one or more excipients selected from diluents, binders, disintegrants, glidants, lubricants, solvents, film coating materials and the like.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to, diluents such as powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, starch, co-processed excipients such as combilac (70% lactose monohydrate, 20% microcrystalline cellulose, 20% maize starch) and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone, modified cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sugars, starches and the like; disintegrants such as sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium and the like; glidants such as calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silicon dioxide, talc, colloidal silica, colloidal silica anhydrous, maize starch and the like; lubricants such as calcium stearate, zinc stearate, magnesium stearate, aluminium stearate, stearic acids, sodium stearyl fumarate, hydrogenated castor oil, light mineral oil, magnesium lauryl sulfate and the like; solubility or wetting enhancers such as surfactants; complex forming agents such as cyclodextrins, resins and the like. Solvents used for granulation can be either aqueous or non-aqueous solvents. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, solvents, lubricants, flavoring agents, sweeteners and the like.
Agomelatine tablet formulations of Example No. 4 and 5 were subjected to in-vitro dissolution studies using USP Type II (Paddle) apparatus at 50 RPM at 37°C in various dissolution media. The results are tabulated in table 2 and table 3.

From tables 2 and 3 it is evident that, Agomelatine tablets prepared according to the invention released more than 90% of the drug in 30 minutes.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example 1: Preparation of Adipic acid co-crystal of Agomelatine
25mg of Agomelatine and 15.02 mg of Adipic acid were blended and co-sifted. The co-sifted material was subjected to dry grinding using Ball Mill. Speed of the mill was adjusted in between 22-26 rpm. Grinding was continued for 45 minutes, and the material was passed from 200# mesh and collected in a suitable container.
Example 2: Preparation of Saccharin co-crystal of Agomelatine
25mg of Agomelatine and 33.2 mg of Saccharin were blended and co-sifted. The co-sifted material was subjected to dry grinding using Ball Mill. Speed of the mill was adjusted in between 22-26 rpm. Grinding was continued for 45 minutes, and the material was passed from 200# mesh and collected in a suitable container.
Adipic acid co-crystal of Agomelatine and Saccharin co-crystal of Agomelatine prepared according to the invention were tested for stability under accelerated conditions. The results are tabulated in table 4:

It is evident from table 4, that Adipic acid co-crystal of Agomelatine and Saccharin co-crystal of Agomelatine were found to be stable even after storing at 60° for 10 days.
Example 3: Preparation of Saccharin co-crystal of Agomelatine
25mg of Agomelatine and 33.2 mg of Saccharin were dry mixed. The dry mixed Co-crystal was melted at 90°C. The melted Co-crystal was allowed to cool and solidify at room temperature. N-hexane was added to the above solidified mass and dried completely till N-Hexane got evaporated. The above dried mass was collected in a suitable container.
Manufacturing Process:
Agomelatine, lactose monohydrate, sodium starch glycolate, micro crystalline cellulose, povidone were co-sifted and blended. The obtainejd blend was compressed as slugs. Slugs were milled and sifted and lubricated with co-sifted magnesium stearate, colloidal silica anhydrous and stearic acid. The blend was compressed into tablets and coated.

Manufacturing Process:
Agomelatine, lactose monohydrate, sodium starch glycolate, micro crystalline cellulose, povidone were co-sifted and blended. The obtained blend was compressed as slugs. Slugs were milled and sifted and lubricated with co-sifted magnesium stearate, colloidal silica anhydrous and stearic acid. The blend was compressed into tablets and coated.

We claim
Claim 1: An Adipic acid co-crystal of Agomelatine.
Claim 2: An Adipic acid co-crystal of Agomelatine according to claim 1, characterized by one or more of the properties chosen from
(i) a powder X-ray diffraction pattern at 20 values of 21.5, 19.6, 19.8, 25.7 ± 0.2
degrees 29 (ii) an infrared absorption spectrum comprising infrared absorption bands at: 3072
and 1625 cm"1 (iii) an endothermic trace comprising an endothermic peak at about 87.7°C in a Differential Scanning Calorimetry (DSC) thermogram.
Claim 3: A process for preparing the co-crystal according to claim 1, wherein the process comprises:
(i) Blending and co-sifting Agomelatine with Adipic acid in suitable proportions, (ii) Dry grinding the co-sifted material using a suitable equipment (iii) Sifting the obtained material.
Claim 4: A Saccharin co-crystal of Agomelatine.
Claim 5: Saccharin co-crystal of Agomelatine according to claim 4, characterized by one or more of the properties chosen from
(i) a powder X-ray diffraction pattern at 29 values of 25.1, 16.0, 19.1 ± 0.2 degrees
29. (ii) an infrared absorption spectrum comprising infrared absorption bands at: 3240
and 1717 cm" . (iii) an endothermic trace comprising an endothermic peak at about 91.0°C in a Differential Scanning Calorimetry (DSC) thermogram

Claim 6: A process for preparing the co-crystal according to claim 4, wherein the process comprises:
(i) Blending and co-sifting Agomelatine with Saccharin in suitable proportions, (ii) Dry grinding the co-sifted material using a suitable equipment (iii) Sifting the obtained material.
Claim 7: A process for preparing the co-crystal according to claims 1 or 4, wherein the process comprises:
(i) Dry mixing Agomelatine and co-crystal-former in suitable proportions.
(ii) Co-melting the above dry mixed material
(iii) Cooling the above melted co-crystal
(iv) Addition of solvent to step (iii), followed by evaporating the solvent.