DESC:FIELD OF THE INVENTION
The present invention relates to isavuconazole form C, isavuconazonium sulfate and process for the preparations thereof. More particularly, the present invention relates to a polymorphic form C of isavuconazole, process for preparation of isavuconazonium sulfate salt and crystalline polymorphic form C of isavuconazonium sulfate.

BACKGROUND AND PRIOR ART OF THE INVENTION
Polymorphism plays an important role in pharmaceutical sciences especially in the chemistry of API’s. Azole derivatives such as Isavuconazole, Isavuconazonium and Ravuconazole are known as an APIs for their antifungal properties as reported in the literature. Polymorphism significantly influences theses antifungal APIs as it plays vital role in determining the physical, chemical, and biochemical properties such as hygroscopicity, flowability, formulating, dissolution, solubility, chemical and physical stability, and even biological efficacy and toxicity of these APIs.

US6300353 discloses Isavuconazole and its process. Isavuconazole is an antifungal drug which has chemical name (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol and has the structural formula as shown below:

Isavuconazole
Isavuconazole is used in the treatment of invasive aspergillosis, candidiasis and mucormycosis in the literature.

Amorphous polymorphic form of isavuconazole and isavuconazonium sulfate is known in the literature.
PCT publication WO2016/055918A1 describes stable amorphous form and crystalline form of isavuconazole base and process for the preparation thereof.
US6812238; US7189858 and US7459561 describe Isavuconazonium and its process for the preparation thereof.

PCT publication WO2016/016766A2 describes stable solid amorphous form of isavuconazonium sulfate and process for its preparation.

Although these polymorphic forms of the isavuconazole and isavuconazonium sulfate are known in the literature, different crystalline solid forms with stable physicochemical properties of isavuconazole and isavuconazonium sulfate remain unexplored hitherto.

As such, there is a need in the art to develop a simple, cost effective industrially feasible process for the preparation of crystalline form of isavuconazonium sulfate so as to reduce or substantially eliminate the impurities and a further provision for stable crystalline polymorphic forms of isavuconazole and isavuconazonium sulfate.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a polymorphic form C of isavuconazole and process for its preparation as well as stable crystalline polymorphic forms of isavuconazonium sulfate and its preparation thereof.

In an aspect, the present invention provides a polymorphic form C of isavuconazole.

In another aspect, the present invention provides a process for the preparation of crystalline polymorphic form C of the isavuconazole, wherein said process comprises the steps of:

a) mixing isavuconazole with purified water and suitable solvent;
b) heating the reaction mixture obtained in step a) to get clear solution;
c) stirring the reaction mixture obtained at step b) for a period in the range of 30-40 mins and cooling gradually to 40-50°C;
d) stirring again the reaction mixture obtained at step c) at a temperature in the range of 40-50°C followed by cooling the reaction mixture to a temperature in the range of -5-10°C to crystallize isavuconazole monohydrate; and
e) washing the isavuconazole monohydrate obtained product at step d) with suitable solvent and purified water and further drying under vacuum at 45±5°C to afford crystalline polymorphic form C of isavuconazole.

The suitable solvents used at step a) and step e) are selected from the group consisting of purified water, C1 to C5 alcoholic solvents alcohols such as methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, tert-butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol; alcoholic solvent denatured with toluene or acetone and mixtures thereof.

Another embodiment of the present invention provides a process for the preparation of isavuconazonium sulfate, wherein said process comprises the steps of:
a) dissolving isavuconazonium halide in a mixture of purified water and suitable solvent at room temperature;
b) passing the clear solution obtained in step a) through sulfate column and washing the column with suitable solvent;
c) adding the suitable solvent into a filtrate collected in step b) and stirring at a temperature in the range of 15-30°C;
d) cooling the reaction mass obtained in step c) further to a temperature in the range of -10-0°C and adding suitable solvent into it under stirring; and
e) filtering and washing the solid obtained in step d) with suitable solvent and drying under vacuum at a temperature in the range of 15-30°C to afford isavuconazonium sulfate.

The suitable solvent used at steps a) to c) are selected from ketonic solvents such as acetone, diiso butyl ketone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, ethane nitrile, butyronitrile and mixtures thereof.

The suitable solvent used at steps d) and e) are selected from ester solvents such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate; ether solvents ethers such as tetrahydrofuran, diethyl ether, isopropyl ether, diisopropyl ether (DIPE), 1,4-dioxane, methyl tertiary butyl ether (MTBE), and like, Propyl cellosolve, Butyl cellosolve, Carbitol, THF, 2-methyl THF; C6 to C10 alkane solvents such as cyclohexane, hexane, n-heptane and mixtures thereof.

Still another embodiment of the present invention provides a process for the preparation of crystalline polymorphic form C of isavuconazonium sulfate, wherein said process comprises the steps of:
a) mixing the isavuconazonium sulfate with purified water and suitable solvent at a temperature in the range of 15-30°C to get clear solution.
b) adding the suitable solvent into a reaction mass obtained in step a) and stirring at a temperature in the range of 15-30°C;
c) cooling the reaction mass obtained in step b) further to a temperature in the range of -10 to 0°C followed by addition of suitable solvent into it under stirring; and
d) filtering and washing the solid obtained instep c) with suitable solvent and drying under vacuum at a temperature in the range of 15-30°C to afford a crystalline polymorphic form of isavuconazonium sulfate salt.

The suitable solvent used in the above process of steps a) to d) is selected from ketonic solvents such as acetone, diiso butyl ketone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, ethane nitrile, butyronitrile; esters such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

The provision of novel crystalline polymorphic form of isavuconazonium sulfate, as proposed in the present invention substantially reduces the presence of impurities viz., Isavuconazonium Impurity E, Isavuconazonium Impurity H, Isavuconazonium Impurity D and Isavuconazonium Impurity B in the final product as compared to the prior art product, isavuconazonium sulfate amorphous form.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts XRD for polymorphic form C of Isavuconazole
Figure 2 depicts XRD for crystalline polymorphic form C of isavuconazonium sulfate

DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the invention. The detailed description will be provided herein below with reference to the attached drawing.

The present invention provides a crystalline polymorphic form C of isavuconazole and process for the preparation thereof.

In an embodiment, the present invention further provides a process for the preparation of polymorphic form C of the isavuconazole, wherein, the isavuconazole was dissolved in purified water using a suitable solvent under heating to reflux temperature obtain to get clear solution. The solution was repeatedly stirred for a period of 30-40 mins and cooled gradually to 35-45°C and further cooled to a temperature of -5 to 10°C to precipitate crystalline isavuconazole monohydrate Form C. The monohydrate thus obtained was washed with suitable solvent and dried under vacuum at 40 to 50°C to afford crystalline polymorphic form C of isavuconazole.

The water content of isavuconazole Form C monohydrate is 4 ± 2%.

The isavuconazole used as a starting material in the above process may be a crude free base or the free base may be of any polymorphic form or a mixture of any of polymorphic forms. The isavuconazole crude may be prepared by the processes reported in US6300353.

In an embodiment, the suitable solvents used in the preparation of isavuconazole Form C are selected from the group consisting of purified water, C1 to C5 alcoholic solvents such as methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, tert-butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol; alcoholic solvent denatured with toluene or acetone and mixtures thereof.

In another embodiment, the present invention provides a crystalline polymorphic form C of isavuconazole, which is characterized by subjecting to PXRD, as shown in figure 1. The crystalline polymorphic form C of isavuconazole is relatively stable towards moisture and humidity, and thus the use of the crystalline polymorphic form C of isavuconazole in pharmaceutical compositions may enhance the efficacy of the parent molecule in lower doses.

Another embodiment of the present invention provides a process for the preparation of isavuconazonium sulfate, wherein isavuconazonium halide was dissolved in purified water and a suitable solvent at room temperature to obtain clear solution. The clear solution thus obtained was passed through sulfate column and washed the column with suitable solvent. The filtrate thus obtained was collected and stirred at a temperature of 15-30°C and cooled the solution to a temperature of -10 to 0°C and further added a suitable solvent into it under stirring. The solid thus obtained was filtered, washed with suitable solvent and dried under vacuum at a temperature of 15-30°C to afford isavuconazonium sulfate.

The suitable solvent used in the preparation of isavuconazonium sulfate as above are selected from ketonic solvents such as acetone, diiso butyl ketone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, ethane nitrile, butyronitrile and mixtures thereof; ester solvents such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate; ether solvents ethers such as tetrahydrofuran, diethyl ether, isopropyl ether, diisopropyl ether (DIPE), 1,4-dioxane, methyl tertiary butyl ether (MTBE), Propyl cellosolve, Butyl cellosolve, Carbitol, THF, 2-methyl THF; C6 to C10 alkane solvents such as cyclohexane, hexane, n-heptane and mixtures thereof.

Isavuconazonium halide is selected from Isavuconazonium chloride, Isavuconazonium fluoride, Isavuconazonium bromide and Isavuconazonium iodide. The Isavuconazonium halide may be prepared as per the processes reported in US6812238 US7189858 and US7459561.

Still another embodiment of the present invention provides a process for the preparation of crystalline polymorphic form C of isavuconazonium sulfate, wherein isavuconazonium sulfate was dissolved in purified water and suitable solvent under stirring at a temperature of 15-30°C to get clear solution. The reaction mass was cooled to a temperature in the range of -10 to 0°C and added a suitable solvent under stirring to obtain crystalline solid. The solid thus obtained was filtered and washed with suitable solvent and dried under vacuum at a temperature range of 15-30°C to afford polymorphic form C of isavuconazonium sulfate salt.

Suitable solvent used in the preparation of polymorphic form of isavuconazonium sulfate salt as in the above process is selected from ketonic solvents such as acetone, diiso butyl ketone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, ethane nitrile, butyronitrile; esters such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

The isavuconazole sulphate used as a starting material in the above process may be a crude sulphate salt or may be in any other polymorphic form or a mixture of any of polymorphic forms.

In yet another embodiment of the present invention provides a crystalline polymorphic form C of isavuconazonium sulfate. The crystalline polymorphic form C of isavuconazonium sulfate is characterized by subjecting to PXRD, as shown in figure 2.

In an embodiment, the new crystalline polymorphic form C of isavuconazonium sulfate thus obtained by the process of the present invention is analyzed for purity by HPLC and compared with the amorphous form of isavuconazonium sulfate obtained by prior art process like US7459561B. It has been seen that the product obtained by the process of the present invention has lesser impurities compared to prior art process. The results are summarized below in Table-1.
Table-1
Impurity Name Crystalline form C Batch 1 Crystalline form C Batch 2 Crystalline form C Batch 3 Prior art process for amorphous form
Isavuconazonium Impurity E 0.02 0.07 0.10 0.026%
Isavuconazonium Impurity H 0.08 0.07 0.05 0.15%
Isavuconazonium Impurity D 0.11 0.09 0.05 0.55%
Isavuconazonium Impurity B 0.11 0.17 0.08 0.7%

Chemical names and structures for the above impurities are as follows:

Isavuconazonium Impurity E : 1-((2R,3R)-3-(4-(4-carbamoylphenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium

Isavuconazonium Impurity H : 1-((2R,3R)-3-(4-(4-(tert-butylcarbamoyl)phenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-((methyl(3-(((methylglycyl)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium

Isavuconazonium Impurity D : 1-((2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-(((3-(5,8-dimethyl-2-(3-(((methylglycyl)oxy)methyl) pyridin-2-yl)-3,7,10-trioxo-4,6,11-trioxa-2,8-diazadodecan-12-yl)pyridin-2-yl)(methyl) carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium

Isavuconazonium Impurity B : 1-((2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl)-2-(2,5-difluorophenyl) -2-hydroxybutyl) -4-(1-(((3-(hydroxymethyl)pyridin-2-yl)(methyl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium

EXAMPLES
Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

Example 1: Preparation of polymorphic form C of Isavuconazole
To the reactor, 4 volumes of purified water and 6 volumes of absolute ethanol denatured with acetone were added and Isavuconazole crude (120 gm) or any other polymorphic form was then added to the reactor. The mixture was heated to 50-60 °C to dissolve the material and to get clear solution. This mixture was then stirred for 30 mins at 50-60 °C and cooled to 42 ± 2 °C. The mixture was again stirred at 42 ± 2 °C, cooled gradually to -0 to 5°C to crystallize monohydrate of Isavuconazole and stirred again. The material obtained thus obtained was filtered, washed with 1 vol mixture of 6:4 absolute alcohol denatured with acetone: purified water) and finally dried under vacuum at 45±5°C to obtain crystalline polymorphic form C of Isavuconazole.
Yield: 110 g
Purity: 99.5%
The PXRD of polymorphic form C of Isavuconazole thus obtained is depicted in figure 1.

Example 2: Preparation of Isavuconazonium sulphate
Isavuconazonium iodide hydrochloride salt (165 gm) was dissolved in 1.5 volumes of purified water and 10 volumes of acetone thereof at room temperature. The clear reaction mass then passed through sulfate resin column and the column was washed with a solvent 5 volumes of acetonitrile. All filtrate was collected in a flask and to it a 15 volumes of acetonitrile was charged and stirred at 20 - 25°C for 4 to 5 hours. The reaction mass was then chilled to -5°C and stirred followed by addition of 20 volumes of ethyl acetate at -5°C and again stirred for 5 hours. The solid obtained was washed with ethyl acetate and dried high vacuum at 25-30°C.
Yield: 108 g
Purity: ? 99 %

Example 3: Preparation of crystalline polymorph C of Isavuconazonium Sulfate
Isavuconazonium sulphate (108 gm) was charged to a clean flask at 25-30°C and 1.5 volumes of purified water and 10 volumes of acetonitrile were added to it till clear solution was obtained. Further, 15 volumes of acetonitrile was added to it and stirred at 25-30°C. The reaction mass was then chilled to -5°C followed by addition of 20 volumes of ethyl acetate at -5°C and stirred for 5 hours. The solid obtained was filtered, washed with ethyl acetate and dried under high vacuum at 25-30°C to obtain crystalline form C of Isavuconazonium Sulfate.
Yield: 80 g
Purity: ? 99%

The PXRD of crystalline polymorphic form of Isavuconazonium Sulfate thus obtained is depicted in figure 2.

ADVANTAGES OF THE INVENTION

• Novel Polymorphic form C of isavuconazole with better physicochemical properties and purity is provided with simple process for its preparation
• Simple and eco-friendly process for the isolation of isavuconazole sulfate is provided
• New crystalline polymorph C of isavuconazonium sulfate is provided with simple process for its preparation with good purity when compared to the prior art process for the preparation of amorphous form. It has been seen that the product obtained by the process of the present invention has lesser impurities compared to prior art process, as shown in table 1.
,CLAIMS:1. A process for preparation of Isavuconazonium sulphate wherein the said process comprises the steps of:
a) dissolving isavuconazonium halide in a mixture of purified water and a solvent at room temperature;
b) passing the clear solution obtained in step a) through a chromatography column and washing the column with the solvent;
c) adding the solvent into a filtrate collected in step b) and stirring at a temperature in the range of 15-30°C;
d) cooling the reaction mass obtained in step c) further to a temperature in the range of -10 to 0°C and adding another solvent into it under stirring; and
e) filtering and washing the solid obtained in step d) with the solvent and drying under vacuum at a temperature in the range of 15-30°C to afford isavuconazonium sulfate.

2. The process according to claim 1 wherein the solvent used in steps a) to c) are selected from ketonic solvents; nitrile solvents and mixtures thereof.

3. The process according to claim 2 wherein the solvent used in steps a) to c) are selected from ketonic solvents such as acetone, diiso butyl ketone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, ethane nitrile, butyronitrile and mixtures thereof.

4. The process according to claim 1 wherein the solvent used in steps d) and e) are selected from ester solvents; ether solvents; C6 to C10 alkane solvents and mixtures thereof.

5. The process according to claim 4 wherein the solvent used in steps d) and e) are selected from ester solvents such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate; ether solvents ethers such as tetrahydrofuran, diethyl ether, isopropyl ether, diisopropyl ether (DIPE), 1,4-dioxane, methyl tertiary butyl ether (MTBE), and like, Propyl cellosolve, Butyl cellosolve, Carbitol, THF, 2-methyl THF; C6 to C10 alkane solvents such as cyclohexane, hexane, n-heptane and mixtures thereof.

6. A novel crystalline polymorphic form C of isavuconazonium sulfate.

7. A novel crystalline polymorphic form C of isavuconazonium sulfate according to claim 6 characterized by XRD pattern as depicted in Fig. 2.

8. A process for the preparation of crystalline polymorphic form C of isavuconazonium sulfate, wherein said process comprises the steps of:
a) mixing the isavuconazonium sulfate with purified water and solvent at a temperature in the range of 15-30°C to get clear solution.
b) adding the solvent into a reaction mass obtained in step a) and stirring at a temperature in the range of 15-30°C;
c) cooling the reaction mass obtained in step b) further to a temperature in the range of -10 to 0°C followed by addition of solvent into it under stirring; and
d) filtering and washing the solid obtained in step c) with a solvent and drying under vacuum at a temperature in the range of 15-30°C to afford a crystalline polymorphic form of isavuconazonium sulfate salt.

9. The process according to claim 8 wherein the solvent used in steps a) to d) are selected from ketonic solvents; nitrile solvents; esters and mixtures thereof.

10. The process according to claim 9 wherein the solvent used in steps a) to d) are selected from ketonic solvents such as acetone, diiso butyl ketone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, ethane nitrile, butyronitrile; esters such as methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

11. A novel crystalline polymorphic form C of isavuconazonium sulfate with low impurity levels of:

Impurity E

Impurity H

Impurity D

And Impurity B.