DESC:“CRYSTALLINE FORM P OF ISAVUCONAZONIUM SULFATE”

FIELD OF THE INVENTION

The present invention relates to a crystalline form P of Isavuconazonium sulfate. The present invention also relates to process for the preparation of crystalline form P of Isavuconazonium sulfate with high purity and yield.

BACKGROUND OF THE INVENTION

Isavuconazonium sulfate (Isavuconazonium sulfate) is an antifungal drug, approved by the US FDA in 2015 for the treatment of invasive aspergillosis and invasive mucormycosis, with the trade name CRESEMBA. The chemical name of Isavuconazonium sulfate is Glycine, N-methyl-, [2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl] ethoxy] carbonyl] methylamino]-3-pyridinyl] methyl ester, sulfate (1:1) and the chemical structure of Isavuconazonium sulfate is shown in formula I.

Isavuconazonium sulfate belongs to the group of compounds first reported in US 6812238 of Basilea Pharmaceutica. Specific example of Isavuconazonium sulfate are not given in US’238. A method for preparing Isavuconazonium chloride, purified by using silica gel column chromatography is given in Example 7 of US’238. However, due to its sensitivity to moisture, Isavuconazonium salts, such as the commercial product Isavuconazonium sulfate, are difficult to purify from crude material to get high purity.

The USFDA label of the medicinal product CRESEMBA, states that Isavuconazonium sulfate drug substance is an amorphous, white to yellowish-white powder.

US 20210323959 discloses crystalline forms I and II of Isavuconazonium sulfate and processes for making them.

The disadvantage of the aforementioned prior art process is that the form I and II of Isavuconazonium sulfate is time-consuming process and results in a low-yield and low-purity.

CN 106467534 discloses a purification process of Isavuconazonium sulfate which comprises, dissolving crude Isavuconazonium sulfate in a mixture of the solvents acetone, purified water and 2-methoxyethanol at room temperature, followed by the dropwise addition of ethyl acetate at 0-10°C, while the temperature of the reaction solution was controlled at 0-5°C and stirred for 16 hrs to get crystalline Isavuconazonium sulfate.

The major disadvantage of the aforementioned prior art process is that the recrystallization using 2-methoxyethanol is expensive and time-consuming, and results in a low-purity of Isavuconazonium sulfate.

CN 106565699 discloses a process for making a crystalline form of Isavuconazonium sulfate, which comprises dissolving crude Isavuconazonium sulfate in a mixture of ethanol and ethyl acetate. The reaction mixture is heated to 40? and then cooled to 20?. The product is then filtered and dried to get crystalline form of Isavuconazonium sulfate.

The major disadvantage of the aforementioned prior art process is that the recrystallization using a mixture of ethanol and ethyl acetate can result in the presence of unwanted impurities, leading to a lower purity of Isavuconazonium sulfate.

The known processes for the preparation of crystalline forms of Isavuconazonium sulfate suffer from several disadvantages. These include lower purity, contamination with impurities, and the requirement of column chromatographic purifications, which can be difficult to handle. These purity issues hinder the production of pure crystalline Isavuconazonium sulfate.

There is still a need for simple, cost-effective and consistently reproducible processes that can produce highly pure and stable crystalline Isavuconazonium sulfate.

SUMMARY OF THE INVENTION

The present invention provides a new crystalline form P of Isavuconazonium sulfate. This novel crystalline form exhibits greater stability, making it highly suitable for pharmaceutical preparations.

In one aspect, a crystalline form P of Isavuconazonium sulfate is provided.

In another aspect, crystalline form P of Isavuconazonium sulfate is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.27, 7.26, 11.94 and 20.91 ± 0.2 degrees of two-theta.

In a preferred aspect, crystalline form P of Isavuconazonium sulfate has characterized by an X-ray powder diffraction pattern having peaks at about 6.48, 12.51, 12.95, 17.20, 17.81, 20.49, 24.83 ± 0.2 degrees of two-theta.

In a most preferred aspect of crystalline form P of Isavuconazonium sulfate is characterized by an X-ray powder diffraction pattern having peaks at about 4.27, 6.48, 7.26, 11.94, 12.51, 12.95, 17.20, 17.81, 20.49, 20.91 and 24.83 ± 0.2 degrees of two-theta.

In one aspect, a process is provided for the preparation of a crystalline form P of Isavuconazonium sulfate, ensuring high purity and yield.

In one aspect, the process for the preparation of crystalline form P of Isavuconazonium sulfate comprises the steps of:
a) dissolving crude Isavuconazonium sulfate in a mixed solution of water, alcohol and ketone;
b) optionally adding an organic solvent to the solution obtained in step (a); and
c) isolating the crystalline form P of Isavuconazonium sulfate.

In another aspect, the process for the preparation of crystalline form P of Isavuconazonium sulfate comprises the steps of:
a) dissolving crude Isavuconazonium sulfate in a mixed solution of water and an organic solvent; and
b) isolating the crystalline form P of Isavuconazonium sulfate.

In yet another aspect, a method is provided for converting crystalline form P of Isavuconazonium sulfate to an amorphous form of Isavuconazonium sulfate comprises the steps:
a) suspending crystalline Isavuconazonium sulfate form P in water;
b) isolating amorphous form of Isavuconazonium sulfate.

In yet another aspect, the process for the preparation of crystalline form P of Isavuconazonium sulfate comprises neutralizing the compound of formula (5) with a base in the presence of water, followed by treatment with a sulfate resin in the presence of a mixture of solvents to obtain Isavuconazonium sulfate (1)

In yet another aspect, a processes is provided for the preparation of Isavuconazonium sulfate producing a substantially pure Isavuconazonium sulfate that is devoid of impurities.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig. 1: illustrates X-ray powder diffraction pattern of crystalline Isavuconazonium sulfate Form P.

Fig. 2: illustrates DSC curve for crystalline Isavuconazonium sulfate Form P.

Fig. 3: illustrates TGA of crystalline Isavuconazonium sulfate Form P.

Fig. 4: illustrates X-ray powder diffraction of Isavuconazonium sulfate amorphous form.

Fig. 5: illustrates HPLC chromatogram of Isavuconazonium sulfate Form P.

DETAILED DESCRIPTION

The present invention relates to the crystalline form P of Isavuconazonium sulfate. The invention additionally, provides a high-purity and high-yield process for preparing crystalline form P of Isavuconazonium sulfate.

In one embodiment, a crystalline form P of Isavuconazonium sulfate is provided.

In another embodiment, crystalline form P of Isavuconazonium sulfate is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.27, 7.26, 11.94 and 20.91± 0.2 degrees of two-theta.

In a preferred embodiment, crystalline form P of Isavuconazonium sulfate has further characterized by an X-ray powder diffraction pattern having peaks at about 6.48, 12.51, 12.95, 17.20, 17.81, 20.49, 24.83 ± 0.2 degrees of two-theta.

In a most preferred embodiment of crystalline form P of Isavuconazonium sulfate is characterized by an X-ray powder diffraction pattern having peaks at about 4.27, 6.48, 7.26, 11.94, 12.51, 12.95, 17.20, 17.81, 20.49, 20.91 and 24.83± 0.2 degrees of two-theta.

As used herein, X-ray diffraction refers to X-ray diffraction by the powder diffraction technique. In accordance with the invention, said X-ray powder diffraction analysis can suitably be performed using a PAN analytical X-Ray Diffractometer (Model: Empyrean), by scanning samples from 2° to 49°2?.

In one embodiment, crystalline form P of Isavuconazonium sulfate is characterized by a DSC pattern as illustrated in Figure 2.

In accordance with the invention, said Differential scanning calorimetric (DSC) analysis can suitably be performed on TA Instruments (model DSC25), with samples held in a closed platinum pan and analyzed at a heating rate of 5°C/min.

In another embodiment, crystalline form P of Isavuconazonium sulfate is characterized by a TGA thermos gram demonstrating a weight loss of approximately 5.8% upon heating up to 100°C.

In accordance with the invention, said thermos gravimetric analysis (TGA) can suitably be conducted using a TA Instruments model TGA 55, by loading approximately 5-6 mg of the sample into a pre-weighed platinum pan and measuring the weight loss of the sample was measured by subjecting it to heating from room temperature to 300°C at a rate of 20°C per minute.

In another embodiment, a process is provided for preparing the crystalline form P of Isavuconazonium sulfate comprises the steps:
a) dissolving crude Isavuconazonium sulfate in a mixed solution of water and one or more organic solvents; and
b) isolating the crystalline form P of Isavuconazonium sulfate.

In a preferred embodiment, the process comprises the steps:
a) dissolving crude Isavuconazonium sulfate in a mixed solution of water, alcohol, and ketone;
b) optionally, adding an organic solvent to the solution obtained in step (a); and
c) isolating the crystalline form P of Isavuconazonium sulfate.

According to a preferred embodiment, the process of preparing crystalline form P of Isavuconazonium sulfate comprises mixing the solvents water, alcohol and ketone in a reaction flask, stirring the solvent mixture and cooling to 20-30°C. Crude Isavuconazonium sulfate is then added to the solvent mixture and stirred until fully dissolved. Subsequently, an organic solvent is added dropwise at a temperature of 20-30°C. The temperature of the reaction solution is maintained at 20-30°C and stirred for a duration of 5-10 hours. The resulting mixture is filtered and washed with acetone in order to obtain the crystalline form P of Isavuconazonium sulfate.

In another embodiment, a process is provided for preparing the crystalline form P of Isavuconazonium sulfate comprises the steps:
a) dissolving crude Isavuconazonium sulfate in a mixed solution of water and an organic solvent;
b) isolating the crystalline form P of Isavuconazonium sulfate.

According to a preferred embodiment, in the process for preparing crystalline form P of Isavuconazonium sulfate, a crude compound of Isavuconazonium sulfate is dissolved in a mixed solution of water and organic solvent. The resulting solution is stirred and cooled to a temperature of 20-30°C. The temperature of the reaction solution is maintained at 20-30°C and stirred for a duration of 5-10 hours. The mixture is then filtered, and the obtained solid is subsequently dried to yield the crystalline Form P of Isavuconazonium sulfate.

In another embodiment, a method is provided for converting crystalline Isavuconazonium sulfate form P to an amorphous form of Isavuconazonium sulfate comprises the steps:
a) suspending crystalline Isavuconazonium sulfate form P in water; and
b) isolating the amorphous form of Isavuconazonium sulfate.

In a preferred embodiment, the method of converting crystalline Isavuconazonium sulfate form P to an amorphous form of Isavuconazonium sulfate comprises that the crystalline solid of Isavuconazonium sulfate form P is dissolved in purified water at a temperature range of 0-15°C and the solvent is then removed resulting in the formation of Isavuconazonium sulfate in an amorphous form.

The amorphous form of Isavuconazonium sulfate is recovered from the solution can be obtained using various drying techniques, including lyophilization or freeze-drying, rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying, and thin-film drying. Filtration is preferably used for isolating the amorphous form. Optionally, the resulting product may undergo further drying at a temperature of approximately 25°C to about 35°C for a duration of about 2 hours to 20 hours. Drying can be performed using methods such as tray drying, vacuum oven drying, air oven drying, fluidized bed drying, spin flash drying, flash drying, or similar techniques. Preferably, drying is carried out under vacuum at a temperature range of about 50°C to about 75°C for a duration of about 2 hours to 10 hours.

In yet another embodiment, a process for the preparation of crystalline form P of Isavuconazonium sulfate is provided which comprises neutralizing the compound of formula (5) with base in presence of water, followed by treating with sulfate resin in presence of mixture of solvents to get Isavuconazonium sulfate (1).

According to one embodiment, the process for preparation of crystalline form P of Isavuconazonium sulfate comprises neutralizing the compound of formula (5) with a base in the presence of water, and subsequently, treating the resulting mixture with sulfate resin in the presence of a solvent mixture at a temperature range of 0-5°C for a duration of 4 hours. This process yields Isavuconazonium sulfate (1) in the form of a white powder.

In an embodiment, the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, lithium hydroxide, lithium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia.

In an embodiment, the organic solvent is selected from methylene dichloride, chloroform, ethyl acetate, toluene, xylene, methanol, ethanol, isopropanol, butanol, propanol, tert-butyl alcohol, acetone, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, or methyl ethyl ether.

In an embodiment, the mixture of solvents is selected from mixtures of sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diisobutyl ketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone.

In yet another embodiment, processes are provided for preparing substantially pure Isavuconazonium sulfate, devoid of its impurities.

As used herein, the term “substantially pure” refers to crystalline form P of Isavuconazonium sulfate having a purity, measured as % area HPLC, of about 97% or more. Preferably, substantially pure crystalline form P of Isavuconazonium sulfate has a purity of about 98% area by HPLC, more preferably of about 99% area by HPLC, even more preferably of about 99.3% area by HPLC, most preferably of about 99.7% area by HPLC

In a preferred embodiment, the process yields a pure Isavuconazonium sulfate which is substantially free from impurities including impurity-1, impurity-2, impurity-3, amide impurity, BOC dimer impurity, Tert butyl impurity, and alcohol impurity.

In another embodiment, a reliable and efficient method is provided for obtaining pure Isavuconazonium sulfate by effectively minimizing the concentrations of the specified impurities, as determined by HPLC analysis.

Impurty-1

Impurty-2

Impurty-3

Amide impurity

Tert butyl impurity

BOC Dimer impurity

Alcohol impurity

In a preferred embodiment, Isavuconazonium sulfate is provided with a purity of at least about 99%, preferably 99.4% to 99.8%, more preferably 99.7%, as determined by HPLC.

Another aspect concerns the products obtainable by any of the processes as defined herein.

Within the context of the present disclosure, a pure and stable crystalline Isavuconazonium sulfate form P means a crystalline form P that exhibits long-term physical and chemical stability for at least 1 month, preferably for at least 3 months, more preferably for at least 6 months when stored exposed to humidity levels ranging from 20% RH to 40% RH at 25°C.

Preferably, Isavuconazonium sulfate crystalline Form P has a better preservation or storage stability as compared to prior art crystal forms in view of, for example, purity, handle ability, fluidity and are useful as crystals appropriate for pharmaceutical formulations.

According to another preferred embodiment, Isavuconazonium sulfate crystalline form P is a hydrate with a water content ranging between 5 to 8% by weight, when it is in contact with the atmosphere at room temperature and with a relative humidity comprised between 20% RH to 60% and it remains stable for at least 6 months in such conditions.

Pharmaceutical compositions comprising crystalline form P of Isavuconazonium sulfate are also provided. The said pharmaceutical compositions are suitable for administration via oral, parenteral, dermal, topical, inhalation or other routes of administration suitable for treatment of subjects in need thereof.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

General Techniques and Methods

X-ray powder diffraction analysis was performed using a PAN analytical X-ray diffractometer (Model: Empyrean). Samples were scanned from 2° to 49°2?.

The differential scanning calorimetric (DSC) analysis was performed on TA Instruments (model DSC25). The samples held in a closed platinum pan were analyzed at a heating rate of 5°C/min.

Thermogravimetric analysis (TGA) was conducted using a TA Instruments model TGA 55. Approximately 5-6 mg of the sample was loaded into a pre-weighed platinum pan. The weight loss of the sample was measured by subjecting it to heating from room temperature to 300°C at a rate of 20°C per minute.

HPLC method

Chromatographic purity by HPLC method has been developed using octadecyl silane column, 250x4.6mm,5µm with a flow rate of 1.0 mL/min and UV detection at 280nm. Acidic buffer is used as mobile phase-A and mobile phase-B is prepared with a mixture of acetonitrile, methanol and water. Gradient programme is used to separate all the peaks and the retention time of analyte peak is about 32 minutes.

Example-1: Preparation of compound 5

A compound of formula 2 (100 g), a compound of formula 3 (190 g), sodium bromide (48 g), tetrabutyl ammonium bromide (100 g), and anhydrous acetonitrile (500 mL) were added into a three-necked flask under nitrogen protection. The resulting reaction mixture was stirred, the temperature was raised to 35°C, and it was stirred again for 48 hours. Afterward, it was cooled to below 20°C and filtered. Dichloromethane (400 mL) and purified water (1000 mL) were added to the reaction mixture, the two layers were separated, and it was washed with saturated brine (100 mL). The mixture was then concentrated under reduced pressure to obtain a foamy solid (compound 4), which was used directly in the next reaction.
In another three-necked flask, a compound of formula 4 (100 g), anhydrous ethyl acetate (1000 mL), and acetonitrile (200 mL) were added under nitrogen protection. This was followed by the dropwise addition of ethyl acetate HCl solution (600 mL) and stirred for 2 hours. The resulting reaction mixture was filtered under nitrogen protection and then dried under vacuum at 25-30°C for 6 hours to obtain a solid (compound 5), or the wet solid could be directly used in the next stage

Yield: 90%

HPLC purity: 95%.

Example-2: Preparation of crystalline form P of Isavuconazonium sulfate.

The compound of formula 5 (50g), dichloromethane, and deionized water were added into a three-necked flask and cooled to 0°C. This was followed by the dropwise addition of a sodium bicarbonate solution. The resulting reaction mixture was cooled to below 5°C to separate the layers. Methanol was added to the reaction flask, followed by the addition of sulfate resin. The mixture was stirred at 0-5°C for 4 hours.
Afterward, the reaction mixture was filtered and washed with acetone. Ethyl acetate was added to the obtained filtrate and maintained for 12 hours. The mixture was then filtered and dried under vacuum at 25-30°C to obtain a crystalline form P of Isavuconazonium sulfate.

Yield: 30g

Purity: 99.4%

Sulfate content: 11.7%

Example 3: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of ethanol (40 mL), water (20 mL) and acetone (250 mL). This was followed by the dropwise addition of ethyl acetate (200 mL). The resulting reaction mixture was stirred at 25°C-30°C for 4-5 hours. It was then filtered, washed with acetone and dried at 25-35°C to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 17g (85%)

HPLC Purity: 99.6%

Example 4: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of THF (250 mL), ethanol (40 mL) and water (20 mL). This was followed by the dropwise addition of ethyl acetate (200 mL). The resulting reaction mixture was stirred at 25°C-30°C for 4-5 hours. It was then filtered, washed with THF and dried at 25-35°C to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 16g (80%)

HPLC Purity: 99.4%

Example 5: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of acetone (250 mL), water (20 mL) and methanol (20 mL). This was followed by the dropwise addition of ethyl acetate (200 mL). The resulting reaction mixture was stirred at 25oC-30oC over 4-5 hours. It was then filtered, washed with acetone and dried at 25-35? to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 16 (80%)

HPLC Purity: 99.7%

Example 6: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of acetone (250 mL) and water (10 mL). The resulting reaction mixture was stirred at 25oC-30oC over 4-5 hours. It was then filtered, washed with acetone and dried at 25-35? to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 15 (75%)

HPLC Purity: 99.2%

Example 7: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of ethanol (120 mL) and water (10 mL). The resulting reaction mixture was stirred at 25°C-30°C for 4-5 hours. It was then filtered, washed with ethanol and dried at 25-35°C to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 15 (75%)

HPLC Purity: 99.3%

Example 8: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of IPA (160 mL) and water (10 mL). The resulting reaction mixture was stirred at 25oC-30oC over 4-5 hours. It was then filtered, washed with IPA and dried at 25-35? to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 15 (75%)

HPLC Purity: 99.3%

Example 9: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of THF (200 mL) and water (10 mL). The resulting reaction mixture was stirred at 25oC-30oC over 4-5 hours. It was then filtered, washed with THF and dried at 25-35? to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 15 (75%)

Purity: 99.2%

Example 10: Preparation of Crystalline Form P of Isavuconazonium sulfate

Crude Isavuconazonium sulfate (20 g) was dissolved in a mixture of acetone (500 mL), water (40 mL) and methanol (20 mL). This was followed by the dropwise addition of ethyl acetate (500 mL). The resulting reaction mixture was stirred at 25oC-30oC over 4-5 hours. It was then filtered, washed with acetone and dried at 25-35? to obtain Crystalline Form P of Isavuconazonium sulfate.

Dry weight: 17 (85%)

Purity: 99.7%

Example 11: Preparation of Amorphous Form of Isavuconazonium sulfate

The crystalline solid of Isavuconazonium sulfate was dissolved in purified water at a temperature ranging from 0 to 15°C. The resulting solution was then subjected to freeze-drying (lyophilization) to obtain Isavuconazonium sulfate in the amorphous form of Isavuconazonium sulfate.

Comparative Example 1 (US20210323959A1):

75 g of the crude sulfate salt of the compound of formula I, HPLC purity 94.8%, was dissolved in a mixture of 225 mL ethanol and 25 mL water, pH 2.8, and stirred at 8° C. over 2 days. After filtration and drying 18 g of the sulfate salt of the compound of formula I was obtained as white crystalline Form I with 98% HPLC purity in 24% yield.

Comparative Example 2 (US20210323959A1):

0.9 g of the crude sulfate salt of the compound of formula I, HPLC purity 85.2%, was dissolved in 4.5 mL ethanol and 0.5 mL water and the pH value was adjusted to 3.7 with concentrated sulfuric acid. The solution was cooled to -10° C. from 20° C. over 15 hours and a precipitate of the sulfate salt of the compound of formula I was formed. The precipitate was filtered and dried to give 0.36 g crystalline Form II with 98% HPLC purity in 36% yield.

Example 12:

Physical stability:

Table 1 below shows data collected on pure and stable crystalline Isavuconazonium sulfate form P as prepared using the process of Examples 3, 5 and 10. The pure and stable crystalline Isavuconazonium sulfate form P tested shows no significant degradation or change in PXRD and is stable at 1, 3 and 6 months storage when stored at 25 ± 2?/60 ±5%, 30 ± 2?/65 ±5%, and at 40 ?/75 ±5% relative humidity (RH).

Table 1:

Condition Crystalline Isavuconazonium sulfate Form P
Water content (%) Related substance (by HPLC) PXRD
At -20±5? RH
Initial 6.3 Any individual impurity 0.38%
Total impurities 1.2% Crystalline form P
6 month 6.6 Any individual impurity 0.70%
Total impurities 1.5% Stable
At 2-8? RH
Initial 6.3 Any individual impurity 0.38%
Total impurities 1.2% Crystalline form P
6 month 6.6 Any individual impurity 0.59%
Total impurities 1.9% Stable
At 25±2?/60±5%RH
Initial 6.3 Any individual impurity 0.38%
Total impurities 1.2% Crystalline form P
6 month 6.5 Any individual impurity 0.73%
Total impurities 2.4% Stable

Throughout the entire testing period, no noticeable change was observed in the total amount of impurities for each polymorph of Isavuconazonium sulfate when compared to the initial levels before the start of the test.
,CLAIMS:WE CLAIMS:

1. A crystalline form P of Isavuconazonium sulfate characterized by an X-ray powder diffraction pattern having characteristic peaks at about 4.27, 7.26, 11.94 and 20.91± 0.2 degrees of two-theta.

2. The crystalline form P of Isavuconazonium sulfate as claimed in claim 1, which is characterized by its X-ray powder diffraction pattern having peaks at about 6.48, 12.51, 12.95, 17.20, 17.81 and 20.49 ± 0.2 degrees of two-theta.

3. The crystalline form P of Isavuconazonium sulfate as claimed in any one of the claims 1-2, having a water content in the range of about 5 to 8%.

4. A crystalline form P of Isavuconazonium sulfate characterized by a DSC pattern as illustrated in Figure 2.

5. A crystalline form P of Isavuconazonium sulfate characterized by a TGA thermos gram demonstrating a weight loss of approximately 5.8% upon heating up to 100°C.

6. A process for the preparation of crystalline form P of Isavuconazonium sulfate comprises the steps:

a) dissolving crude Isavuconazonium sulfate in a mixed solution of water, alcohol and ketone;
b) optionally, adding an organic solvent to the Isavuconazonium sulfate solution obtained in step (a); and
c) isolating the crystalline Form P of Isavuconazonium sulfate.

7. The process as claimed in claim 6, wherein step a) the mixed solvents of alcohol and ketone are selected form methanol, ethanol, isopropyl alcohol, butanol, tert-butyl alcohol and propanol; acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, diisobutyl ketone, tetrahydrofuran and water mixtures thereof; and wherein step b) the organic solvent is selected from methanol, ethanol, isopropyl alcohol, butanol, propanol, tert-butyl alcohol, acetone and tetrahydrofuran.

8. A process for the preparation of crystalline form P of Isavuconazonium sulfate, which comprises neutralizing the compound of formula (5) with a base in the presence of water, followed by treating it with sulfate resin in a mixture of solvents to obtain Isavuconazonium sulfate (1).

9. The process as claimed in claim 8, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, lithium hydroxide, lithium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride and ammonia; and wherein the mixture of solvents selected from methanol, ethanol, isopropanol, dichloromethane, dichloroethane, dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, tetrahydrofuran, ethyl acetate and water.

10. The process as claimed in any one of the claims 8-9, wherein the reaction is carried out at 25-30°C for 4-5 hours.