DESC:Field of the Invention:
The present invention relates to novel crystalline form of (S)-5-(3-(1-((2-hydroxy
ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile
5 hydrochloride compound of formula-1, represented by the following structural formula:
Formula-1
10 The present invention also relates to process for the preparation novel crystalline form of
the compound of formula-1.
Background of the Invention:
Ozanimod hydrochloride, has a chemical name (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-
dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride and is
15 represented by the structure of formula-1. Ozanimod is an immunomodulatory drug approved by
FDA in March 2020 and May 2020 in Europe for the treatment of relapsing multiple sclerosis
(RMS) and also under clinical trials for the treatment of ulcerative colitis, Crohn's disease.
The US patent No. 8481573 B2 (herein after designated as US’573) first reported racemic
Ozanimod, its synthetic process. The same process disclosed in Scheme-I.
20 The US patent No. 8362048B2 (herein after designated as US'048) covers a process for
preparation of ozanimod (S) and (R) isomers and intermediates thereof. The process involves
asymmetric synthesis using chiral reagents such as S-tertiary butyl sulfinamide in presence of
titaniumethoxide, which is expensive reagent not suitable on commercial process.
The patent application WO2018215807A1 covers a process for preparation of ozanimod
25 by chiral resolution method.
3
The patent application WO2019058290A1 covers a process for preparation of ozanimod by chiral resolution method using phenethylamine as chiral agent.
The CN107840830A reported crystalline form-I of ozanimod hydrochloride as anhydrous.
The US10882830B2 covering CS3 of ozanimod HCl of ozanimod hydrochloride and processes thereof. 5
The US11117876B2 reported crystalline form CS2 ozanimod hydrochloride and its process for preparation.
The US20200157065A1 covering crystalline form CS1 ozanimod hydrochloride and its process for preparation.
The WO2019094409A1 disclosed crystalline Forms I, Form-II and Form-III of ozanimod 10
hydrochloride. Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful 15 compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or 20 improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of ozanimod hydrochloride.
The novel crystalline form of (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4- oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride described herein help 25 meet this and other needs.
The present invention provides a novel crystalline form and its process for the preparation of compound of formula-1.
30
4
Brief Description:
The first aspect of the present invention is to provide novel crystalline form of (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxy benzonitrile hydrochloride compound of formula-1, herein after designated as crystalline form-M of ozanimod hydrochloride. 5
The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of of (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxa diazol-5-yl)-2-isopropoxy benzonitrile hydrochloride compound of formula-1.
Brief description of the drawings: 10
Figure 1: Illustrates the PXRD pattern of crystalline form--M of (S)--5--(3--(1--((2--hydroxy ethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol--5--yl)--2--isopropoxybenzonitrile hydrochloride compound of formula--1.
Detailed Description: 15
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene 20 glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra 25 chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-30
5
pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The first aspect of the present invention provides crystalline form-M of (S)--5--(3--(1--((2--hydroxyethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol--5--yl)--2--isopropoxy 5 benzonitrile hydrochloride compound of formula-1. The crystalline form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 3.9, 5.7, 7.7, 9.7, 11.6, 13.5, 15.5, 19.5, 21.4, 23.5, 22.7, 23.5, 24.6, 27.5, 29.6, 31.5, 35.6, 37.6, 41.9, & 46.1. ± 0.2° 2?. The said crystalline form--M is further characterized by its powder X--Ray diffraction pattern substantially in accordance with figure--1. 10
The second aspect of the present invention provides a process for the preparation of the crystalline form--M of (S)--5--(3--(1--((2--hydroxyethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol--5--yl)--2--isopropoxy benzonitrile hydrochloride compound of formula--1; comprising of:
a) Stirring the ozanimod and HCl in a suitable solvent at a suitable temperature,
b) optionally heating the solution, at a suitable temperature, 15
c) filtering the obtained solid in step--c) provides the crystalline form--M of (S)--5--(3--(1--((2--hydroxyethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol--5--yl)--2--isopropoxy benzonitrile hydrochloride compound of formula--1.
Wherein in step--a), b) the suitable temperature is 0 to 110°C;
in step--a), b) the solvent system may be a single solvent or mixture of solvents and is selected 20 from hydrocarbon solvents, ester solvents, ether solvent, chloro solvents, ketone solvents, polar aprotic solvent, polor protic solvent, alcohol, water, Conc.HCl, dil.HCl and mixture thereof;
The preferred embodiment of the present invention is to provide crystalline form--M of Ozanimod hydrochloride. Comprising of: 25
a) stirring ozanimod and 1N HCl in methanol at 0 to 5°C,
b) filtering the precipitated solid obtained in step--a) to get the crystalline form--M of ozanimod hydrochloride.
(S)--5--(3--(1--((2--hydroxyethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol--5--yl)--30 2--isopropoxy benzonitrile hydrochloride produced by the present invention can be further
6
micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. milling or micronization may be performed before drying, or after the completion of drying of the product. 5
PXRD analysis of PXRD analysis of (S)--5--(3--(1--((2--hydroxyethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol--5--yl)--2--isopropoxy benzonitrile hydrochloride was carried out using BRUKER was carried out using BRUKER D8 ADVANCED/AXS XD8 ADVANCED/AXS X--Ray diffractometer using Cu KRay diffractometer using Cu Ka a radiation of wavelength 1.5406 A° radiation of wavelength 1.5406 A° and continuous scanand continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkinspeed of 0.03°/min. IR spectra were recorded on a Perkin--Elmer FTIR Elmer FTIR spectrometer.spectrometer. 10
(S)--5--(3--(1--((2--hydroxyethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol --5--yl)--2--isopropoxy benzonitrile hydrochloride compound of formula--1 used in the present invention is synthesized by the prior known processes.
The process described in the present invention was demonstrated in examples illustrated 15 below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example--1: Preparation of crystalline form--M of compound of formula--1
A round bottom flask was charged with ozanimod (0.2 g) and 1N HCl (0.5 mL) were stirred for 20 15 min. Methanol (10 mL) was charged the reaction mixture and stirred for 1 hr at 0--5°, the precipitated solid was stirred and filtered, dried to get the title compound.
PXRD of the obtained compound is designated as form--M and depicted in figure--1.
Yield: 0.2 g
Example--2: Preparation of crystalline form--M of compound of formula--1 25
A round bottom flask was charged with ozanimod (0.5 g) and 1N HCl (1.2 mL) were stirred for 15 min. Methanol (25 mL) was charged the reaction mixture and stirred for 1 hr at 0--5°, the precipitated solid was stirred and filtered, dried to get the title compound.
Yield: 0.5 g
30
7
,CLAIMS:We claim
1. A process for the preparation of crystalline form-M of Ozanimod hydrochloride
comprising:
a) Stirring the ozanimod and HCl in a suitable solvent at a suitable temperature, 5
b)optionally heating the solution, at a suitable temperature,
c)filtering the solid obtained in step--b) provides the crystalline form--M of (S)--5--(3--(1--((2--hydroxyethyl)amino)--2,3--dihydro--1H--inden--4--yl)--1,2,4--oxadiazol--5--yl)--2--isopropoxy benzonitrile hydrochloride compound of formula--1.
2.The process as claimed in claim 1 wherein in step--a), b) the suitable temperature is 0 to 10 110°C;
3. The process as claimed in claim 1 wherein in step--a), b) the solvent system may be a single solvent or mixture of solvents and is selected from hydrocarbon solvents, ester solvents, ether solvents, chloro solvents, ketone solvents, polar aprotic solvents, polar protic solvents, alcohol solvents, water, Conc.HCl, dil.HCl and mixture thereof; 15
4. A process for crystalline form--M of Ozanimod hydrochloride
Comprising of:
a) stirring ozanimod and 1N HCl in methanol at 0 to 5°C,
b) filtering the precipitated solid obtained in step--a) to get the crystalline form--M of ozanimod hydrochloride. 20
5.The process as claimed in claim 1 and 4, wherein the Ozanimod hydrochloride crystalline form is crystalline form M which is characterized PXRD (powder X-Ray diffraction) pattern having peaks at about 7.7 and 11.6° 2? ± 0.2° 2?.
6.The crystalline form M as claimed in claim 1 and 4, wherein Ozanimod hydrochloride crystalline Form M is further characterized PXRD (powder X-Ray diffraction) pattern 25 having peaks at about 3.9, 5.7,9.7,13.5,15.5, 19.5, 21.4, 24.6, 27.5, 29.6, 31.5, 35.6 and 37.6° 2? ± 0.2° 2?
7. The process as claimed in the above claims, wherein the Ozanimod hydrochloride crystalline form is crystalline form M which is characterized PXRD pattern as depicted in Figure 1. 30
8
8. The pharmaceutical composition comprising crystalline form M of Ozanimod hydrochloride of the above claims and at least one pharmaceutically acceptable excipient.