DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Provisional Patent Application No. 201941036804 filed on September 12, 2019; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Stiripentol particles having defined particle size distribution.

BACKGROUND OF THE INVENTION

Stiripentol is chemical known as 4, 4-dimethyl-1-[3, 4-(methylendioxyphenyl)-1-pentene-3-ol having the formula-I as mentioned below.

Stiripentol has an anti-epileptic effect, marketed in US as Diacomit for the treatment of seizures associated with Dravet syndrome in infancy and is available in 250 mg and 500 mg as oral capsule or oral suspension. Stiripentol belongs to the BCS-II classification of drugs that is low soluble and high permeable. Thus the rate determining step of bioavailability is the dissolution process. The particle size distribution of stiripentol plays a major role in dissolution process.

The Patent US 7750169 discloses the desired particle size distribution of stiripentol for the preparation of the finished dosage forms is such that the diameter of 50? of the particles (hereinafter referred as D50) is less than or equal to 100µm, especially from 50 to 85 µm and the diameter of 90? of the particles (hereinafter referred as D90) is less than or equal to 300µm, especially less than or equal to 250 µm.

The Patent US 3910959 discloses the product and crystallization process of the stiripentol from ethanol. The melting point of Stiripentol is approximately 75°C that makes the size reduction process difficult during the preparation of finished dosage form.

The Patent US 7750169 discloses a method for achieving the desired particle size of stiripentol involving the steps of: (i) dissolution of stiripentol in an aromatic solvent; (ii) crystallization of the stiripentol from the solvent; and (iii) recovery of the obtained stiripentol particles. The aromatic solvents such as toluene and benzene used in the process comes under the Class-II solvents that has to be limited during the preparation of APIs.

Besides the availability of method for the preparation Stiripentol particles in state of the art, there is a need for an improved process for the preparation of Stiripentol particles having a defined particle size distribution that is economically significant and industrially viable.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide an efficient and industry feasible process for the preparation of Stiripentol particles.

Yet another object of the invention is to provide an improved process for the preparation of Stiripentol particles having a defined particle size distribution.

SUMMARY OF THE INVENTION

The main aspect of the invention is to provide a process for the preparation of Stiripentol particles, comprising the steps of:
(a) providing a solution of stiripentol in isopropyl alcohol or its mixtures thereof;
(b) crystallizing the stiripentol from the solution as provided in step (a); and
(c) isolating the stiripentol particles obtained in step (b).

Another aspect of the invention is to provide a process wherein the isopropyl alcohol or its mixtures is isopropyl alcohol or a mixture of isopropyl alcohol with one or more suitable solvents miscible with isopropanol.

A further aspect of the invention is to provide a process wherein the obtained Stiripentol particles contains Stiripentol Impurity–A (E)-4,4,-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene-3-one, Stiripentol Impurity–B (±)-(E)-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl-1-pentan-3-ol and Stiripentol Impurity-C (±)-(E)-3-methoxy-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene below 0.05 % in HPLC.

Yet another important aspect of the present invention is to provide an improved process for preparation of Stiripentol particles having a defined particle size distribution.

The particle size of Stiripentol obtained in present invention is such that D90 of the particles is less than 300 µm and D50 of the particles is less than 100 µm that is suitable for the preparation of finished dosage formulation.

Preferably, D90 of the particle is in the range from 40-250 µm and D50 of the particle is in the range from 10-80 µm.

More preferably, D90 of the particle is in the range from 50-70 µm and D50 of the particle is in the range from 20-40 µm.

DETAILED DESCRIPTION OF THE INVENTION

An embodiment of the invention is to provide a process for the preparation of Stiripentol particles, comprising the steps of:
(a) providing a solution of stiripentol in isopropyl alcohol or its mixtures thereof;
(b) crystallizing the stiripentol from the solution as provided in step (a); and
(c) isolating the stiripentol particles obtained in step (b).

The step of providing a solution of stiripentol in isopropyl alcohol or its mixtures thereof according to step (a) may be performed by dissolving the crude stiripentol obtained from the methods known in state of the art or by a solution containing stiripentol obtained directly from the reactions known in state of the art.
Isopropyl alcohol or its mixtures according to step (a) is isopropyl alcohol or a mixture of isopropyl alcohol with one or more suitable solvents miscible with isopropanol, preferably a mixture of isopropyl alcohol and water thereof.

The step (a) is carried out by heating the mixture of crude stiripentol and aqueous isopropyl alcohol to a range of 50-70°C and stirred to obtain a clear solution.

The step of crystallizing the stiripentol from the solution according to the step (b) may be done by different methods including: concentrating the solution; cooling the solution; adding additional water; seeding with crystals of stiripentol or any combinations of the methods thereof.

The crystallization of the stiripentol is carried out by cooling to a range of 5-20°C.

The step of isolating the stiripentol particles according to the step (c) may be done in methods known in the state of art, preferably by filtration.

The present invention avoids the use of aromatic solvents for the purification of the product and also avoids product loss that could happen due to sticking of particles during mechanical size reduction techniques such as grinding.

The particle size of Stiripentol obtained in present invention is such that D90 of the particles is less than 300 µm and D50 of the particles is less than 100 µm that is suitable for the preparation of finished dosage formulation.

Preferably, D90 of the particle is in the range from 40-250 µm and D50 of the particle is in the range from 10-80 µm.

More preferably, D90 of the particle is in the range from 50-70 µm and D50 of the particle is in the range from 20-40 µm.

The obtained product have Stiripentol Impurity–A (E)-4,4,-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene-3-one, Stiripentol Impurity–B (±)-(E)-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl-1-pentan-3-ol and Stiripentol Impurity-C (±)-(E)-3-methoxy-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene which are less than 0.05 % in HPLC.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of 1-(benzo[d] [1, 3] dioxol-5-yl)-4, 4-dimethylpent-1-en-3-one
To a solution of piperonal (50 gm), methanol (350 ml) and tetrabutylammonium bromide (2.5 gm), pinacolone (36.7 gm) was added followed by the addition of sodium hydroxide solution (Prepared by dissolving 66.6 gm of sodium hydroxide in water). The reaction mixture was then heated to 50°C and stirred till completion of the reaction. The progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mass was cooled and stirred for about 1 hour. The resultant solid was filtered and washed with water (500 ml) and dried. Yield: 86 %

Example-2: Preparation of 1-(1,3-benzodioxol-5-yl)-4,4-dimethyl-1-penten-3-ol
To a slurry of 1-(benzo[d][1,3]dioxol-5-yl)-4,4-dimethylpent-1-en-3-one prepared from Example-1 (50 gm) in methanol (150 ml), sodium borohydride (4.1 gm) was added at 35°C and stirred for about 1 hour at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to 10°C and stirred for 1 hour at the same temperature. Ammonium chloride solution (250 ml) was slowly added to the reaction mass for 30 minutes and the temperature was increased to 30°C. The reaction mass was stirred for 2 hours at 30°C. The resultant solid was filtered, washed with water (250 ml) and dried. Yield: 91 %

Example-3: Preparation of Stiripentol particles
A mixture of crude stiripentol (50 gm) and aqueous isopropyl alcohol (Prepared by mixing 135 ml of isopropyl alcohol and 90 ml of water) was heated to 60°C and stirred to obtain a clear solution. The heated solution was gradually cooled and seeded with crystalline stiripentol. The cooled mass was further cooled to a range of 5-10°C and stirred at the same temperature till the crystallization. The resultant solid was filtered, washed with water (150 ml) and dried under vacuum. The solid was further dried under vacuum at 45-50°C for about 6 hours. Yield: 86 %; Melting point: 75°C;
D50 of the particle is 32.4 µm;
D90 of the particle is 59.2 µm.
Stiripentol Impurity–A (E)-4,4,-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene-3-one, Stiripentol Impurity–B (±)-(E)-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl-1-pentan-3-ol and Stiripentol Impurity-C (±)-(E)-3-methoxy-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene are less than 0.05 % in HPLC respectively.
,CLAIMS:

1. A process for the preparation of Stiripentol particles, comprising the steps of:
(a) providing a solution of stiripentol in isopropyl alcohol or its mixtures thereof;
(b) crystallizing the stiripentol from the solution as provided in step (a); and
(c) isolating the stiripentol particles obtained in step (b).

2. The process as claimed in claim-1, wherein the isopropyl alcohol or its mixtures is isopropyl alcohol or a mixture of isopropyl alcohol with one or more suitable solvents miscible with isopropanol.

3. The process as claimed in claim-2, wherein the mixture of isopropyl alcohol and one or more suitable solvents miscible with isopropanol is preferably a mixture of isopropyl alcohol and water thereof.

4. The process as claimed in claim-1, wherein the step (a) is carried out by heating the mixture of crude stiripentol and aqueous isopropyl alcohol to a range of 50-70°C.

5. The process as claimed in claim-1, wherein crystallization in step (b) is carried out by concentrating the solution; cooling the solution; adding additional water; and seeding with crystals of stiripentol.

6. The process as claimed in claim-5, wherein crystallization of the stiripentol is carried out by cooling to a range of 5-20°C.

7. The process as claimed in claim-1, wherein Stiripentol particles obtained from the process contains Stiripentol Impurity–A (E)-4,4,-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene-3-one, Stiripentol Impurity–B (±)-(E)-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl-1-pentan-3-ol and Stiripentol Impurity-C (±)-(E)-3-methoxy-4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene below 0.05 % in HPLC.

8. The Stiripentol particles as claimed in claim-1, wherein particle size of the stiripentol particles are such that D90 of the particles is less than 300 µm and D50 of the particles is less than 100 µm.

9. The Stiripentol particles as claimed in claim-8, wherein particle size of the stiripentol particles are such that D90 of the particle is in the range from 40-250 µm and D50 of the particle is in the range from 10-80 µm.

10. The Stiripentol particles as claimed in claim-9, wherein particle size of the stiripentol particles are such that D90 of the particle is in the range from 50-70 µm and D50 of the particle is in the range from 20-40 µm.