HK1141005B - New process for obtaining the crystalline form v of agomelatine - Google Patents

Description

Novel process for obtaining crystalline form V agomelatine

Technical Field

The present invention relates to a novel process for obtaining the crystalline form V of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I):

background art:

agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide has valuable pharmacological properties.

In fact, it has a dual property, which is, on the one hand, an agonist of receptors of the melatoninergic system and, on the other hand, 5-HT_2CAn antagonist of the receptor. These properties confer central nervous system activity and more particularly activity for the treatment of major depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its preparation and its use in therapy have been described in european patent EP 0447285.

In view of the pharmaceutical value of such compounds, it is important to obtain such compounds in excellent purity, and in particular in a sufficiently reproducible form having valuable properties that allow them to be stored for long periods without special requirements as regards temperature, light, humidity or oxygen level.

Patent application EP 1752443 describes a well-defined crystalline form-V of agomelatine, characterized by the following X-ray powder diffraction diagram, measured with a siemens d5005 diffractometer (copper on cathode) and expressed in interplanar spacing d, Bragg's angle 2 θ and relative intensity (expressed as a percentage with respect to the most intense line):

this well-defined crystalline form, obtained in a reproducible manner, has very valuable morphological properties, in particular a specific surface area which is much higher than that of the other forms. However, the shelf life is short and in all cases less than 6 months.

Disclosure of Invention

The applicant has now developed a new process for obtaining agomelatine in crystalline form V in a well reproducible manner, thereby increasing its stability over time. This new process therefore makes it possible to obtain agomelatine in crystalline form V, with properties compatible with its pharmaceutical use. Crystalline form V has in the past only been obtained by so-called "high energy" milling or by seeding with a structurally pure form which has been obtained by milling.

The applicant has now surprisingly found that this form can be obtained by spray drying. Indeed, spray drying is a common technique for obtaining solid particles of small size. The substances obtained are often Amorphous (Amorphous state in the pharmaceutical industry, Polymorphism, edited by R.Hilfiker, Wiley-VCHWeinheim 2006, Chapter X, p.259-285, S.Petit and G.coquerel). In contrast thereto, in the present invention, spray drying may be used to obtain a well-defined crystalline form-form V, and which has better stability over time.

More specifically, the present invention relates to a new process for obtaining agomelatine of formula (I) in crystalline form V, which is characterized in that a solution of agomelatine dissolved in one or two solvents miscible in any ratio and having a boiling point lower than 120 ℃ is atomized in a spray dryer.

Spray drying is a technique commonly used in the agricultural, food and pharmaceutical fields to dry solutions that are sprayed with an superheated gas. In practice, the gas used to dry the solution is air, but some pharmaceutical methods using organic solvents require inert gases as the drying gas to avoid certain decomposition processes.

The crystallization operation of the present invention is preferably carried out using a spray dryer. The atomization according to the invention is more preferably carried out according to the atomization principle using nozzles with parallel flows and more preferably with concurrent flows (i.e. the sprayed solution and the drying gas flow are in the same direction).

The gas used is advantageously compressed air or an inert gas, for example nitrogen.

Preferred solvents for the process of the invention are ethanol, water, isopropyl ether, methanol, ethyl acetate or acetone.

The minimum concentration of the agomelatine solution used is 5g/l and more preferably 10g/l of solution is used.

The inlet temperature of the process of the invention is advantageously from 70 ℃ to 120 ℃.

In the crystallization process of the present invention, agomelatine of formula (I) obtained by any method can be used.

Detailed Description

The invention is illustrated in a non-limiting manner by the following examples.

Example 1: n- [2- (7-methoxy-1-naphthyl) ethyl]Crystalline form V of acetamide

A10 g/l solution of agomelatine in an ethanol/isopropyl ether mixture (50/50: v/v) was introduced into the atomizer of a BUCHI 190 mini spray dryer. The inlet temperature of the drying chamber was 90 ℃ and the outlet temperature was 66 ℃. The atomized powder was recovered in a collection bowl and characterized by the following crystallographic data:

1) spectra obtained with a Siemens D5005 diffractometer using a 2 θ angular range of 3 ° to 30 °, a span of 0.04 ° and 4 seconds per span:

-crystal structure of unit cell: the crystal is a monoclinic crystal,

-unit cell parameters: a is 11.967b＝17.902c＝15.423β＝124.5°

-space group: p2₁/n

-number of molecules in unit cell: 8 (Z' ═ 2)

Volume of unit cell: v_Cell＝2720.0

2) The following X-ray powder diffractogram, measured with a Siemens D5005 diffractometer (copper vs. cathode), and expressed in interplanar spacing D, Bragg's angle 2 θ and relative intensity (expressed as a percentage with respect to the most intense line):

example 2: n- [2- (7-methoxy-1-naphthyl) ethyl obtained by atomization]Stability of acetamide V form over time

A sample of 1g of the compound obtained in example 1 was placed under conventional storage conditions: ambient pressure and temperature. After 21 months, the diffractogram of the resulting sample did not change, still having the characteristics of the resulting form V.

Claims (4)

1. A process for obtaining the crystalline form V of agomelatine of formula (I):

characterized in that a solution of agomelatine dissolved in one or two solvents selected from ethanol, water, isopropyl ether, methanol, ethyl acetate or acetone is atomized in a spray dryer, wherein the resulting compound has the following X-ray powder diffraction pattern, measured with a Siemens D5005 diffractometer (copper on cathode) and expressed in interplanar spacing D, Bragg's angle 2 θ and relative intensity (expressed as a percentage with respect to the most intense line):

2. the process according to claim 1 for the preparation of the crystalline form V of the compound of formula (I), characterized in that the solvents used are ethanol and isopropyl ether.

3. The process for preparing the crystalline form V of the compound of formula (I) according to claim 1, characterized in that the gas used is nitrogen.

4. The process for the preparation of crystalline form V of the compound of formula (I) according to claim 1, characterized in that the agomelatine solution used has a minimum concentration of 5 g/l.