DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

CRYSTALLINE FORMS OF ISAVUCONAZONIUM SULFATE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:
FIELD OF INVENTION

The present invention provides novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, a process for the preparation thereof and a pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.

BACKGROUND OF THE INVENTION

Isavuconazonium sulfate, is the prodrug of Isavuconazole, and it is an azole antifungal agent used for the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazonium Sulfate is very soluble in water and over the pH range 1-7. Isavuconazonium sulfate is being marketed in the US under the brand name Cresemba®.

The structure of Isavuconazonium sulfate is shown as follows:

Formula (I)

Isavuconazonium sulfate is disclosed in US 6,812,238 of Basilea.

US 6,812,238 of Basilea discloses a process for the preparation of Isavuconazonium salts including sulfate salt by reaction with mineral acid to produce Isavuconazonium sulfate. However, due to its sensitivity to moisture, Isavuconazonium sulfate is difficult to purify from crude material in high yield and purity.

CN 106565699 discloses a process for the preparation of crystal form of Isavuconazonium sulfate by dissolving Isavuconazole hydrochloride in water, adjusting the pH to neutral using a base at a low temperature, adding an organic solvent A for extraction, drying and concentrating and then dissolving in an organic solvent B, adding conc. H2SO4 and H2O2 at a low temperature; Followed by adding the obtained concentrate to an organic solvent C, heating to dissolve, stirring and cooling to crystallize, and performing suction filtration to produce a crystal.

The disadvantage of this method is the said process is not suitable for commercial scale-up due to the use of hydrogen peroxide leads to significant degradation of the product. The yield is 62 % and purity is 97.7%.

CN 106467534 discloses a process for the preparation of crystal form of Isavuconazonium sulfate by dissolving the crude Isavuconazonium sulfate in a mixed solution of water, an organic solvent A and an organic solvent B, then adding an organic solvent C to the Isavuconazonium sulfate solution obtained above; followed by stirring and separation to produce crystalline Isavuconazonium sulfate.

The disadvantage of this method is the results in low yield and purity.

US 20210323959 discloses a process for the purification of Isavuconazonium sulfate, by dissolving the Isavuconazonium sulfate in an aliphatic alcohol and water, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; allowing a first portion of Isavuconazonium sulfate to crystalize from the mixture; and adding an aprotic organic solvent to the mixture and allowing an additional portion of Isavuconazonium sulfate to precipitate from the mixture to produce crystalline form.

The main disadvantage of this method, which produces unwanted impurities and results the product in low yield and low purity.

Hence, there is a need to develop a cost effective and commercially viable process for the preparation of crystalline form of Isavuconazonium sulfate having higher purity.

The present invention provides novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5% by HPLC with high yield and process for the preparation thereof.

OBJECTIVE OF INVENTION

The main object of the present invention is to provide novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5% by HPLC.
Another object of the present invention is to provide a process of the preparation of novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5% by HPLC.

Another object of the present invention is to provide a pharmaceutical composition comprising the novel crystalline forms Isavuconazonium sulfate having purity greater than 99.5% by HPLC.

SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide novel crystalline forms Isavuconazonium sulfate.

Another embodiment of the present invention is to provide a process for the preparation of crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, which comprises:
(i) dissolving Isavuconazonium sulfate in water and a solvent;
(ii) cooling;
(iii) stirring;
(iv) optionally seeding with crystalline form of Isavuconazonium sulfate,
(v) filtering;
(vi) drying; and
(vii) isolating crystalline form of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.

In an embodiment, the present invention provides a crystalline form of Isavuconazonium sulfate (Form ISA-1), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 6.3, 7.9, 9.3, 10.5, 13.9, 15.6, 17.8 and 25.4 ± 0.2º 2?;
• DSC as shown in Figure 6;
• TGA as shown in Figure 11.

Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-2), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.2, 6.3, 8.0, 9.7, 11.2, 12.6, 13.7, 17.1, 17.5 and 19.6 ± 0.2º 2? ;
• DSC as shown in Figure 7;
• TGA as shown in Figure 12.

Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-3), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.1, 6.3, 8.0, 9.6, 11.0, 12.9, 13.7, 14.6, 17.5 and 20.5 ± 0.2º 2?;
• DSC as shown in Figure 8;
• TGA as shown in Figure 13.

Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-4), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.2, 5.7, 6.5, 9.2, 10.2, 14.5, 16.0, 16.6, 18.6 and 20.6 ± 0.2º 2?.
• DSC as shown in Figure 9;
• TGA as shown in Figure 14.

Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-5), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.6, 6.5, 8.4, 9.2, 10.2, 14.5, 16.1, 16.8, 18.5, and 23.1 ± 0.2 2?.
• DSC as shown in Figure 10;
• TGA as shown in Figure 15.

Another embodiment of the present invention is to provide a process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5), which comprises, exposing a crystalline form of Isavuconazonium sulfate to humidity to obtain crystalline form of Isavuconazonium sulfate (Form ISA-5).

Another embodiment of the present invention is to provide a process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Illustrates the X-ray powder diffraction pattern of Form ISA-1.
Figure 2: Illustrates the X-ray powder diffraction pattern of Form ISA-2.
Figure 3: Illustrates the X-ray powder diffraction pattern of Form ISA-3.
Figure 4: Illustrates the X-ray powder diffraction pattern of Form ISA-4.
Figure 5: Illustrates the X-ray powder diffraction pattern of Form ISA-5.
Figure 6: Illustrates the DSC of Form ISA-1.
Figure 7: Illustrates the DSC of Form ISA-2.
Figure 8: Illustrates the DSC of Form ISA-3.
Figure 9: Illustrates the DSC of Form ISA-4.
Figure 10: Illustrates the DSC of Form ISA-5.
Figure 11: Illustrates the TGA of Form ISA-1.
Figure 12: Illustrates the TGA of Form ISA-2.
Figure 13: Illustrates the TGA of Form ISA-3.
Figure 14: Illustrates the TGA of Form ISA-4.
Figure 15: Illustrates the TGA of Form ISA-5.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention is to provide novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, a process for the preparation thereof and a pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.

In a preferred embodiment, the crystalline forms may be substantially hydrates, which may be monohydrate, dihydrate or a trihydrate, which are stable.

The novel crystalline forms can be characterized by X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray powder diffraction pattern was measured on Bruker D8 advance-Eco with lynex detector equipped with Cu source (?=1.58Å) or any equivalent X-ray powder diffractometer instrument.
Scanning parameters:
Scan type: Continuous scan;
Scan range: 2-40°;
Time/step: 0.8 sec;
Step size: 0.05°;
Divergence slit: V20;
Rotation: 30 rpm.

Another embodiment of the present invention is to provide a process for the preparation of crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, which comprises, Isavuconazonium sulfate is dissolved in water and a solvent; The reaction mass is cooled and stirred. If the solid is not isolated, then seeding with crystalline form of Isavuconazonium sulfate. The obtained solid is filtered and dried, if required slurried in a solvent, then filtered and dried to obtain crystalline form of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.

The solvent used in the above process comprises water, acetonitrile, ethanenitrile, propionitrile, butyronitrile, isobutyronitrile, ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, isopentyl acetate, hexyl acetate, n-hexane, heptane or mixtures thereof.

The suitable temperature of the above process comprises dissolution temperature ranges from 25?C to 30?C; the cooling temperature ranges from -10?C to 5?C and the drying temperature ranges from 25?C to 40?C.

The crystalline form of Isavuconazonium sulfate produced by the above process comprises Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 or Form ISA-5.

In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-1) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 1 which has peaks at 6.3, 7.9, 9.3, 10.5, 13.9, 15.6, 17.7 and 25.4 ± 0.2º 2?;
• DSC thermogram having broad endothermic peak at about 62.33°C, 82.50°C and 87.00°C; and
• TGA thermogram having a weight loss of about 7.5%.

In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-2) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.2, 6.3, 8.0, 9.7, 11.2, 12.6, 13.7, 17.1, 17.5 and 19.6 ± 0.2º 2?;
• DSC thermogram having broad endothermic peak at about 70.56°C, 115.05°C and 141.38°C; and
• TGA thermogram having a weight loss of about 4.2%.

In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-3) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.1, 6.3, 8.0, 9.6, 11.0, 12.9, 13.7, 14.6, 17.5 and 20.5 ± 0.2º 2?;
• DSC thermogram having broad endothermic peak at about 81.34°C, 119.52° and 141.35°C; and
• TGA thermogram having a weight loss of about 4.2%.

In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-4) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.2, 5.7, 6.5, 9.2, 10.2, 14.5, 16.0, 16.6, 18.6 and 20.6 ± 0.2º 2?;
• DSC thermogram having endothermic peaks at about 96.98°C; 138.15°C and 150.63°C; and
• TGA thermogram having a weight loss of about 4.7%.

In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-5) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.6, 6.5, 8.4, 9.2, 10.2, 14.5, 16.1, 16.8, 18.5, and 23.1 ± 0.2 2?;
• DSC thermogram having broad endothermic peak at about 61.42°C, 83.95°C and 150.85°C; and
• TGA thermogram having a weight loss of about 3.6%.

In yet another preferred embodiment, the present invention provides a process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5) which comprises exposing crystalline form of Isavuconazonium sulfate (Form ISA-4) to a humidity between 20-80% RH at room temperature.

In yet another preferred embodiment, the present invention provides a process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.

The crystalline Isavuconazonium sulfate used in the preparation of amorphous Isavuconazonium sulfate could be any of the crystalline form such as
Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 and Form ISA-5.

Another object of the present invention is to provide a pharmaceutical composition comprising the crystalline hydrated forms of Isavuconazonium sulfate.

Isavuconazonium sulfate used in the present invention is prepared according to the process disclosed in the literature. The Isavuconazonium sulfate used in the present invention comprising in the form of amorphous or crystalline form produced by prior-art procedures.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example-1: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-1):
Isavuconazonium, sulfate (1:1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for 1-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-1).

Example-2: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-2)
Isavuconazonium, sulfate (1:1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for 1-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s. Further material was dried at 35±5°C under vacuum for 3-4hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-2).

Example-3: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-3)
Isavuconazonium, sulfate (1:1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for 1-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s. Further material was slurried in ethyl acetate 10.0ml at 20°C for 2-3hr’s. Solid was filtered and washed with ethyl acetate 1.0ml followed by suck dried under nitrogen atmosphere for 5min’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-3).

Example-4: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium, sulfate (1:1) 0.5gm was dissolved in DM water (1.0ml) at room temperature and acetonitrile (25ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-24hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for 1-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0ml) followed by suck dried for 5min’s. Further material was dried at 30±5°C under vacuum for 2-3hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.36%.

Example-5: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium sulfate (1:1) 0.5gm was dissolved in DM water (2.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass cooled to -10°C and stirred reaction mass for 45-50 hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for 1-2hr’s. Obtained solid was filtered and washed acetonitrile (5.0ml) followed by suck dried for 5min’s. Further material was dried at 30±5°C under vacuum for 2-3hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.62%.

Example-6: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium sulfate (1:1) 1.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 20-24hr’s at -10°C and 1% seed was added to above reaction mass. Stirred the reaction mass for 20-24hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for 1-2hr’s. Obtained solid was filtered and washed acetonitrile (20.0ml) followed by suck dried for 5min’s. Further material was dried at 30±5°C under vacuum for 3-5hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.41%.

Example-7: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium sulfate (1:1) 4.0gm was dissolved in DM water (8.0ml) at room temperature and acetonitrile (200ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 44-48hr’s at -10°C and 1% seed was added to above reaction mass. Stirred the reaction mass for 20-24hr’s at -10°C solid was isolated. The temperature was slowly raised up to 0-5°C and stirred for 1-2hr’s. Obtained solid was filtered and washed acetonitrile (20.0ml) followed by suck dried for 5min’s. Further material was dried at 30±5°C under vacuum for 3-5hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.16%.

Example-8: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5)
Isavuconazonium Sulfate (25g) was dissolved in purified water (50 ml) at 20-30°C under nitrogen atmosphere. Reaction mixture was stirred at 20-30°C for 15-20 minutes. Acetonitrile was slowly added (1250 ml) to the above clear solution at 20-30°C in 45-60 minutes. Reaction mixture was cooled to -10°C to -15°C. The reaction mixture was seeded with Isavuconazonium Sulfate API (0.25g) at -10°C to -15°C. The above solution was maintained at -10° to -15°C for 20-24hr, temperature was slowly raised to 0-5°C for 1-2hr. The compound was filtered at 0-5°C and washed with pre-cooled acetonitrile (0-5°C, 250 ml) and suck dried. Further, wet material was dried the under vacuum at 30±5°C for 03 hr. to afford crystalline form of Isavuconazonium sulfate (Form ISA-5). HPLC purity ~99.57%.

Example-9: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5)
Isavuconazonium sulfate (1:1) was exposed to humidity 40% RH or 60% RH at room temperature for 5 days to afford crystalline form of Isavuconazonium sulfate (Form ISA-5).

Example-10: Preparation of amorphous form of Isavuconazonium sulfate:
Isavuconazonium sulfate crystalline form (100 g) was dissolved in purified water (500 ml), the solution was stirred for 10 to 15 min at 20-30°C. The above solution was loaded into lyophilizer and lyophilized under optimized recipe to give amorphous material, the material was unloaded under nitrogen atmosphere and the moisture content was checked which is NMT 2.0%. ,CLAIMS:WE CLAIM:
1. A crystalline form of Isavuconazonium sulfate (Form ISA-1), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 6.3, 7.9, 9.3, 10.5, 13.9, 15.6, 17.8 and 25.4 ± 0.2º 2?;
• DSC as shown in Figure 6;
• TGA as shown in Figure 10.

2. A crystalline form of Isavuconazonium sulfate (Form ISA-2), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.2, 6.3, 8.0, 9.7, 11.2, 12.6, 13.7, 17.1, 17.5 and 19.6 ± 0.2º 2?; (or)
• DSC as shown in Figure 7; (or)
• TGA as shown in Figure 12.

3. A crystalline form of Isavuconazonium sulfate (Form ISA-3), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.1, 6.3, 8.0, 9.6, 11.0, 12.9, 13.7, 14.6, 17.5 and 20.5 ± 0.2º 2?; (or)
• DSC as shown in Figure 8; (or)
• TGA as shown in Figure 13.

4. A crystalline form of Isavuconazonium sulfate (Form ISA-4), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.2, 5.7, 6.5, 9.2, 10.2, 14.5, 16.0, 16.6, 18.6 and 20.6 ± 0.2º 2?; (or)
• DSC as shown in Figure 9; (or)
• TGA as shown in Figure 14.

5. A crystalline form of Isavuconazonium sulfate (Form ISA-5), which is characterized by
• X-ray powder diffraction pattern having 2? peaks at 4.6, 6.5, 8.4, 9.2, 10.2, 14.5, 16.1, 16.8, 18.5, and 23.1 ± 0.2° 2?; (or)
• DSC as shown in Figure 10; (or)
• TGA as shown in Figure 15.

6. A crystallization process of Isavuconazonium sulfate, which comprises,
(i) dissolving Isavuconazonium sulfate in a water and a solvent;
(ii) cooling;
(iii) stirring; or vice -versa
(iv) optionally seeding with crystalline form of Isavuconazonium sulfate,
(v) filtering;
(vi) drying; and
(vii) isolating crystalline form of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.

7. The process as claimed in claim 6, wherein the crystalline form of Isavuconazonium sulfate comprises Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 or Form ISA-5.

8. A process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5), which comprises, exposing crystalline form of Isavuconazonium sulfate to humidity to obtain crystalline form of Isavuconazonium sulfate (Form ISA-5).

9. A process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.