Crystalline forms of isavuconazonium sulfate and methods for preparing same

Abstract

The present invention relates to a crystalline form of isavuconazonium sulfate. The present invention also relates to a method for preparing isavuconazonium sulfate and a pharmaceutical composition comprising crystalline isavuconazonium sulfate. The present invention also relates to a method for treating fungal infections, such as invasive aspergillosis and mucormycosis, comprising administering a therapeutically effective amount of crystalline isavuconazonium sulfate to a subject in need thereof. The present invention also provides isavuconazonium sulfate having high purity.

Description

[Technical field]

[0001] Priority This application claims the benefit of Indian Provisional Application No. 202221006158, entitled "Process for Preparation of Isavuconazonium Sulfate," filed on February 4, 2022, the contents of which are incorporated herein by reference.

[0002] The present invention relates to a crystalline form of isavuconazonium sulfate, a method for its preparation, and a pharmaceutical composition comprising the crystalline isavuconazonium sulfate.The present invention also relates to a method for treating fungal infections, such as invasive aspergillosis and mucormycosis, comprising administering a therapeutically effective amount of crystalline isavuconazonium sulfate to a subject in need thereof.The present invention also provides isavuconazonium sulfate having high purity. [Background technology]

[0003] Isavuconazonium sulfate is a prodrug of isavuconazole, an azole antifungal drug. Its chemical name is (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate monosulfate, and is herein hereinafter referred to as the compound of formula I.

[0004] Isavuconazonium sulfate (CRESEMBA®) was approved by the U.S. FDA in 2015 for use in treating invasive aspergillosis and mucormycosis, life-threatening fungal infections that primarily affect immunocompromised patients.

[0005] Isavuconazonium sulfate, sold as CRESEMBA®, is available in capsule form for oral administration. Isavuconazonium sulfate is also sold as an injection for intravenous administration, CRESEMBA®.

[0006] In view of the effectiveness of isavuconazonium sulfate and the known fact that various solid forms of the active pharmaceutical agent offer numerous advantages, such as improved solubility, dissolution profile, better stability, shelf life, etc., there is a need to provide new crystalline forms of isavuconazonium sulfate that have beneficial properties.

[0007] Furthermore, it is well known that providing pharmaceutical substances with high purity is considered a critical aspect in the pharmaceutical industry, particularly to ensure the safety, efficacy, and consistency of pharmaceutical compositions containing active pharmaceutical ingredients (APIs).

[0008] Considering the importance of providing pharmaceutical substances with high purity, better storage stability, and ease of preparation of finished dosage forms, it is an object of the present invention to provide novel crystalline forms of isavuconazonium sulfate; processes for the preparation of crystalline isavuconazonium sulfate; pharmaceutical compositions comprising crystalline isavuconazonium sulfate; and the use of crystalline isavuconazonium sulfate in the treatment of life-threatening fungal infections. Summary of the Invention [Means for solving the problem]

[0009] The present invention provides a novel crystalline form of isavuconazonium sulfate, represented by the compound of Formula I set forth below, designated Form GL-1 (referred to herein as "crystalline isavuconazonium sulfate" or "Form GL-1"), which has X-ray powder diffraction peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2 degrees 2θ. Diffraction (XRPD) pattern; XRPD pattern substantially as shown in FIG. 1; approximately 3412.33, 2432.59, 1756, 1578.51, 1447.24, 1379.27, 1325.65, 1305, 1216.36, 1116.29, 1063.94, 926.77, 894.63, 847.74, 819.96, 765.38, and 696.25±2 cm -1 2; a thermogravimetric analysis (TGA) thermogram determined over a temperature range of 0° C. to 250° C. at a heating rate of 10° C. / min and exhibiting a weight loss of about 6.56% up to 150° C.; a TGA thermogram substantially as shown in FIG. 3; and combinations thereof.

[0010] The present invention further provides crystalline isavuconazonium sulfate (form GL-1) characterized by an XRPD pattern having one or more additional peaks at 12.5, 17.83, 21.99, and 22.56±0.2 degrees 2θ.

[0011] The present invention also provides a method for preparing isavuconazonium sulfate, a compound of formula I represented by the following structure:

[0012] [ka]

[0013] The method is: (a) providing a reaction mixture comprising isavuconazonium sulfate and a solvent system comprising a nitrile solvent and water; (b) stirring the reaction mixture of step (a) to precipitate isavuconazonium sulfate; (c) isolating the isavuconazonium sulfate obtained in step (b), wherein the isolated isavuconazonium sulfate is in a crystalline form referred to as crystalline isavuconazonium sulfate (form GL-1).

[0014] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline isavuconazonium sulfate described above and at least one pharma- ceutically acceptable excipient.

[0015] The present invention further provides a method of treating a fungal infection, comprising administering a therapeutically effective amount of crystalline isavuconazonium sulfate to a subject in need thereof. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows a characteristic X-ray powder diffraction (XRPD) pattern of crystalline isavuconazonium sulfate (form GL-1). [Diagram 2] 1 shows a characteristic infrared (IR) spectrum of crystalline isavuconazonium sulfate (form GL-1). [Diagram 3] FIG. 1 shows a characteristic thermogravimetric analysis (TGA) thermogram of crystalline isavuconazonium sulfate (form GL-1). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Various exemplary embodiments described herein relate to a novel crystalline form of isavuconazonium sulfate, a compound of formula I, referred to as Form GL-1 ("crystalline isavuconazonium sulfate" or "Form GL-1"), and represented by the following structure:

[0018] [ka]

[0019] The crystalline isavuconazonium sulfate (form GL-1) of the present invention may be characterized by its X-ray powder diffraction (XRPD) pattern peaks at 2θ values; IR spectrum; thermogravimetric analysis (TGA) thermogram; and / or solid-state, 13 They can be characterized by a variety of analytical parameters, alone or in combination, including, but not limited to, C NMR spectroscopy, and other methods of characterization of solid forms known to those skilled in the art, such as Raman spectroscopy.

[0020] In one embodiment, the invention provides crystalline isavuconazonium sulfate characterized by an XRPD pattern with peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2 degrees 2θ.

[0021] In one or more additional embodiments, as can be combined with the preceding paragraphs, the invention provides crystalline isavuconazonium sulfate characterized by an XRPD pattern having one or more additional peaks at 12.5, 17.83, 21.99, and 22.56±0.2 degrees 2θ.

[0022] Alternatively, in additional embodiments, the crystalline isavuconazonium sulfate of the present invention may be characterized by an XRPD pattern having peaks at 6.45, 7.25, 12.5, 15.98, 16.87, 17.25, 17.83, 20.93, 21.99, and 22.56±0.2 degrees 2θ.

[0023] In additional embodiments, the crystalline isavuconazonium sulfate of the present invention may be characterized by an XRPD pattern having at least four peaks at 6.45, 7.25, 12.5, 15.98, 16.87, 17.25, 17.83, 20.93, 21.99, and 22.56±0.2 degrees 2θ.

[0024] In one embodiment, which can be combined with the preceding paragraph, the present invention provides crystalline isavuconazonium sulfate characterized by an XRPD pattern substantially as shown in FIG.

[0025] In one embodiment, the present invention provides crystalline isavuconazonium sulfate characterized by an XRPD pattern substantially as shown in FIG.

[0026] The term "XRPD pattern substantially as shown in Figure 1" means that for comparison purposes, some variation in peak intensities from those shown in Figure 1 is allowed for. Those skilled in the art will appreciate that the 2θ values ​​of the XRPD pattern of the crystalline isavuconazonium sulfate salt of the present invention may vary slightly from instrument to instrument and also due to sample preparation variations and / or batch to batch variations. Thus, the 2θ values ​​are not to be interpreted as absolute values. Those skilled in the art will also appreciate that the relative intensities of the peaks may vary due to orientation effects.

[0027] In one embodiment, the present invention provides a method for producing a 3D shape comprising the steps of: -1 The present invention provides crystalline isavuconazonium sulfate (form GL-1) characterized by an IR spectrum with a major band at

[0028] In one embodiment, which may be combined with the preceding paragraph, the present invention provides crystalline isavuconazonium sulfate (form GL-1) characterized by an IR spectrum as shown in FIG.

[0029] In one embodiment, the present invention provides a crystalline isavuconazonium sulfate characterized by an IR spectrum as shown in FIG.

[0030] In one embodiment, the present invention provides crystalline isavuconazonium sulfate (Form GL-1) characterized by a thermogravimetric analysis (TGA) thermogram determined over the temperature range of 0° C. to 250° C. at a heating rate of 10° C. / min, exhibiting a weight loss of about 6.56% up to 150° C.

[0031] In one embodiment, which can be combined with the preceding paragraph, the present invention provides crystalline isavuconazonium sulfate (Form GL-1) characterized by a TGA thermogram substantially as shown in FIG.

[0032] In one embodiment, the present invention provides crystalline isavuconazonium sulfate characterized by a TGA thermogram substantially as shown in FIG.

[0033] The term "substantially as shown in Figure 3" means that the reported TGA properties may vary by about ±5°C.

[0034] In one embodiment, the present invention provides an XRPD pattern having peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2 degrees 2θ; -1 and a thermogravimetric analysis (TGA) thermogram determined over a temperature range of 0°C to 250°C at a heating rate of 10°C / min, exhibiting a weight loss of about 6.56% up to 150°C.

[0035] In one embodiment, the present invention provides crystalline isavuconazonium sulfate (form GL-1) having a crystallinity of at least 30%.

[0036] In one embodiment, the present invention provides crystalline isavuconazonium sulfate (form GL-1), wherein the amorphous content of isavuconazonium sulfate is 70% or less.

[0037] In one embodiment, the present invention provides crystalline isavuconazonium sulfate (form GL-1), wherein the amorphous content of isavuconazonium sulfate is 65% or less.

[0038] In one embodiment, the present invention provides a composition comprising crystalline isavuconazonium sulfate (form GL-1), wherein the amorphous content of the isavuconazonium sulfate is 70% or less.

[0039] In one embodiment, the present invention also provides a method for preparing isavuconazonium sulfate, a compound of formula I:

[0040] [ka]

[0041] The method is: (a) providing a reaction mixture comprising isavuconazonium sulfate and a solvent system comprising a nitrile solvent and water; (b) stirring the reaction mixture of step (a) to precipitate isavuconazonium sulfate; (c) isolating the isavuconazonium sulfate obtained in step (b), wherein the isolated isavuconazonium sulfate is in crystalline form ("crystalline isavuconazonium sulfate").

[0042] In one embodiment, in step (a) of the above process, the reaction mixture can be obtained by adding isavuconazonium sulfate to a solvent system comprising a mixture of a nitrile solvent and water.

[0043] In another embodiment, in step (a) of the above process, the reaction mixture can be obtained by adding a solvent system comprising a nitrile solvent and water to isavuconazonium sulfate.

[0044] In one embodiment, the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, and isobutyronitrile.

[0045] In one embodiment, the addition of isavuconazonium sulfate to a solvent system comprising a nitrile solvent and water, or the addition of a solvent system comprising a nitrile solvent and water to the isavuconazonium sulfate, can be carried out at a temperature of from about 0° C. to about 25° C.

[0046] As used herein, the term "about" refers to a value that is within a range defined by a variation of up to ±10% of the value, preferably up to ±5% of the value.

[0047] The addition of the isavuconazonium sulfate to the solvent system, or the addition of the solvent system to the isavuconazonium sulfate, can be carried out over a period of from about 10 minutes to about 1 hour.

[0048] In one embodiment, in step (b), the reaction mixture of step (a) comprising isavuconazonium sulfate and a solvent system comprising a nitrile solvent and water can be stirred for a period of about 1 hour to about 24 hours.

[0049] In one embodiment, the reaction mixture of step (a) may be stirred for a period of about 3 hours to about 15 hours.

[0050] The reaction mixture containing isavuconazonium sulfate and a solvent system containing a nitrile solvent and water can be stirred at a temperature of about 0°C to about 35°C.

[0051] In one embodiment, the reaction mixture comprising isavuconazonium sulfate and a solvent system comprising a nitrile solvent and water can be stirred at a temperature between about 10°C and about 30°C.

[0052] In one embodiment, a reaction mixture comprising isavuconazonium sulfate and a solvent system consisting of a nitrile solvent and water can be stirred at a temperature between about 0° C. and about 35° C. for a period of about 1 hour to about 24 hours to precipitate the isavuconazonium sulfate.

[0053] In one embodiment, in step (c) of the above process, the isavuconazonium sulfate obtained in step (b) is isolated by methods such as filtration, centrifugation, and the like.

[0054] In one embodiment, the present invention provides a process for preparing crystalline isavuconazonium sulfate (form GL-1), the process comprising: (a) providing a reaction mixture comprising isavuconazonium sulfate and a solvent system comprising a nitrile solvent and water; (b) stirring the reaction mixture of step (a) to precipitate isavuconazonium sulfate; and (c) isolating the isavuconazonium sulfate obtained in step (b), wherein the isolated isavuconazonium sulfate is in crystalline form, and the crystalline isavuconazonium sulfate (form GL-1) has an XRPD pattern having peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2°2θ; -1 and a thermogravimetric analysis (TGA) thermogram determined over a temperature range of 0° C. to 250° C. at a heating rate of 10° C. / min, exhibiting a weight loss of about 6.56% up to 150° C.

[0055] In one embodiment, the invention provides a method using steps (a)-(c) above for preparing crystalline isavuconazonium sulfate (Form GL-1), wherein the crystalline form is further characterized by an XRPD pattern having one or more additional peaks at 12.5, 17.83, 21.99, and 22.56±0.2 degrees 2θ.

[0056] In one embodiment, the nitrile solvent used in step (a) of the process for preparing crystalline isavuconazonium sulfate is acetonitrile.

[0057] Thus, the present invention provides a method for preparing crystalline isavuconazonium sulfate, the method comprising: (a) providing a reaction mixture comprising isavuconazonium sulfate and a solvent system comprising acetonitrile and water; (b) stirring the reaction mixture of step (a) to precipitate isavuconazonium sulfate; (c) isolating crystalline isavuconazonium sulfate, the XRPD pattern having peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2 degrees 2θ; -1 and a thermogravimetric analysis (TGA) thermogram determined over a temperature range of 0° C. to 250° C. at a heating rate of 10° C. / min, exhibiting a weight loss of about 6.56% up to 150° C.

[0058] In one embodiment, the present invention provides a method for preparing crystalline isavuconazonium sulfate, the method comprising: (A) providing an aqueous solution of isavuconazonium sulfate; (B) adding a nitrile solvent as an anti-solvent to the aqueous solution of isavuconazonium sulfate of step (A) to precipitate isavuconazonium sulfate; (C) isolating the crystalline isavuconazonium sulfate obtained in step (B).

[0059] As used herein, the term "anti-solvent" refers to a solvent in which a compound is insoluble at a given concentration, so as to effectively precipitate the compound from a solution containing that solvent.

[0060] In one embodiment, the nitrile solvent used as the anti-solvent in step (B) above is selected from the group consisting of acetonitrile, propionitrile, and isobutyronitrile.

[0061] In one embodiment, the nitrile solvent used as the anti-solvent is acetonitrile.

[0062] In one embodiment, the invention provides a method of preparing crystalline isavuconazonium sulfate (Form GL-1), the method comprising treating isavuconazonium sulfate with a solvent system comprising acetonitrile and water, wherein the resulting crystalline isavuconazonium sulfate is characterized by an XRPD pattern with peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2 degrees 2θ. The resulting crystalline isavuconazonium sulfate (Form GL-1) is further characterized by an XRPD pattern with one or more additional peaks at 12.5, 17.83, 21.99, and 22.56±0.2 degrees 2θ.

[0063] In one embodiment, the invention provides a method of preparing crystalline isavuconazonium sulfate (Form GL-1), the method comprising treating isavuconazonium sulfate with a solvent system comprising acetonitrile and water, wherein the resulting crystalline isavuconazonium sulfate is characterized by an XRPD pattern with peaks at 6.45, 7.25, 12.5, 15.98, 16.87, 17.25, 17.83, 20.93, 21.99, and 22.56±0.2 degrees 2θ.

[0064] In one embodiment, the present invention provides a method for preparing crystalline isavuconazonium sulfate (form GL-1), the method comprising isolating crystalline isavuconazonium sulfate (form GL-1) from a solvent system comprising a mixture of a nitrile solvent and water.

[0065] In one embodiment, the invention provides a method for preparing crystalline isavuconazonium sulfate (form GL-1), the method comprising isolating crystalline isavuconazonium sulfate from a solvent system comprising a mixture of acetonitrile and water.

[0066] In one embodiment, as may be combined with the preceding paragraph, the present invention provides a method for preparing crystalline isavuconazonium sulfate (form GL-1), wherein in step (a) of the method, a reaction mixture is (i) providing an aqueous solution of isavuconazonium sulfate; (ii) passing the aqueous solution of isavuconazonium sulfate obtained in step (i) through a polyethersulfone nanofiltration membrane (PES); (iii) treating the solution obtained in step “(ii)” with a nitrile solvent to obtain a reaction mixture.

[0067] In one embodiment, in step (ii), the aqueous solution from step (i) is passed through a polyethersulfone nanofiltration membrane (PES) to obtain an aqueous solution having a concentration of isavuconazonium sulfate of about 30% to about 50% of the total volume.

[0068] In one embodiment, in step (ii), the polyethersulfone-based nanofiltration membrane (PES) has a diameter of about 150 to about 300 Daltons.

[0069] In one embodiment, it has surprisingly been found that crystalline isavuconazonium sulfate (form GL-1) can be obtained without subjecting it to lyophilization.

[0070] Isavuconazonium sulfate, the compound of formula I structurally represented above, is a mixture of epimers, i.e., epimer I and epimer II, which are represented by the following structures:

[0071] [ka]

[0072] As used herein, the term "epimers" refers to diastereomers that differ from each other in stereochemistry at only one of multiple stereocenters.

[0073] In one embodiment, the present invention provides crystalline isavuconazonium sulfate (form GL-1) containing epimer I and epimer II in a 1:1 ratio.

[0074] In the context of the present invention, a person skilled in the art will understand that a reference to the crystalline isavuconazonium sulfate (form GL-1) of the present invention also refers to crystalline isavuconazonium sulfate (form GL-1) comprising epimer I and epimer II in a 1:1 ratio.

[0075] As noted above, isavuconazonium sulfate is currently sold in capsule and injectable form under the trade name Cresemba®. This approved commercial product contains an amorphous form of isavuconazonium sulfate. (See, e.g., Ref.: Cresemba EPAR Public Assessment Report, EMA / 596950 / 2015, 23 July 2015.)

[0076] The amorphous form of isavuconazonium sulfate is known to be unstable and produce impurities identified as compounds of formulas IV, VI, VII, VIII, IX, X and XI, shown below by their respective chemical structures.

[0077] [ka]

[0078] [ka]

[0079] In the development of generic drugs, it is very important to provide active ingredients (APIs) that exhibit a favorable impurity profile, since the safety of the drug depends mainly on the impurities contained therein. It is therefore desirable to have APIs with favorable impurity profiles that provide advantages in terms of ease of drug formulation and improved storage stability. The crystalline isavuconazonium sulfate (form GL-1) disclosed herein, according to non-limiting exemplary embodiments, advantageously exhibits a favorable impurity profile while at the same time improving storage stability. Moreover, the crystalline isavuconazonium sulfate (form GL-1) disclosed herein can be obtained by a simple and cost-effective method.

[0080] In an embodiment, the crystalline isavuconazonium sulfate (form GL-1) obtained in step (c) disclosed herein has a chemical purity of at least 90% as measured by high performance liquid chromatography (HPLC).

[0081] In one embodiment, the crystalline isavuconazonium sulfate (form GL-1) obtained in step (c) disclosed herein has a chemical purity of at least 99% as measured by HPLC.

[0082] In one embodiment, the crystalline isavuconazonium sulfate (form GL-1) obtained in step (c) disclosed herein has a chemical purity of at least 99.9% as measured by HPLC.

[0083] In one embodiment, the present invention provides crystalline isavuconazonium sulfate (Form GL-1), Form GL-1 containing less than about 0.2% w / w of an impurity selected from a compound of formula IV, VI, VII, VIII, IX, X, or XI (above), as measured by HPLC.

[0084] Further, in one embodiment, the present invention provides a method for preparing crystalline isavuconazonium sulfate (Form GL-1), wherein Form GL-1 contains less than about 0.2% w / w of an impurity selected from compounds of formula IV, VI, VII, VIII, IX, X, or XI (above).

[0085] In one embodiment, the present invention provides a method for preparing crystalline isavuconazonium sulfate (Form GL-1), wherein the content of compound of Formula IV, VI, VII, VIII, IX, X, or XI (above) present in the resulting crystalline isavuconazonium sulfate (Form GL-1) is from about 0.03% to about 0.2% w / w as measured by HPLC.

[0086] Apart from a desirable impurity profile of the API, it is equally important that the API exhibits substantial stability throughout the manufacturing of the pharmaceutical product as well as during the packaging, storage, distribution, and use stages of the pharmaceutical product. According to the non-limiting exemplary embodiments disclosed herein, the inventors of the present invention have succeeded in providing a crystalline isavuconazonium sulfate (form GL-1) that is substantially stable as compared to the amorphous form contained in the commercial product Cresemba, as evidenced by the comparative stability data provided in the Experimental Section.

[0087] The term "stable" as used herein refers to crystalline isavuconazonium sulfate (form GL-1) that substantially retains its chemical purity and does not degrade during storage. In its accepted and customary meaning, the term "storage" in reference to a product means that the product remains stable for the shelf life of its intended use. By way of example, a specific stability test for determining the chemical stability of crystalline isavuconazonium sulfate (form GL-1) when stored under specific storage conditions is described in the experimental section.

[0088] Described herein is stable crystalline isavuconazonium sulfate (form GL-1) characterized by an XRPD pattern with peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2 degrees 2θ, having no detectable amount of any of the impurities selected from compounds of formula IV, VI, VII, VIII, IX, X, or XI. The stable crystalline isavuconazonium sulfate (form GL-1) is further characterized by an XRPD pattern with one or more additional peaks at 12.5, 17.83, 21.99, and 22.56±0.2 degrees 2θ.

[0089] In one embodiment, the invention provides a process for preparing stable crystalline isavuconazonium sulfate (Form GL-1), characterized by an XRPD pattern with peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2 degrees 2θ, without any detectable amount of any of the impurities selected from compounds of formula IV, VI, VII, VIII, IX, X, or XI.

[0090] The term "detectable amount" as used herein refers to the amount of the compound of formula IV, VI, VII, VIII, IX, X, or XI above, determined using an analytical method that is capable of detecting each of the above-specified impurities in an amount greater than 0.03% w / w. Thus, the term "not detectable amount" indicates that any of the impurities selected from the compound of formula IV, VI, VII, VIII, IX, X, or XI is present or in an amount less than 0.03% w / w.

[0091] In an exemplary embodiment, stability testing of the crystalline isavuconazonium sulfate salt of the present invention (form GL-1) was performed according to the methods described in the Experimental Section. The stability testing data presented in the Experimental Section confirms that the crystalline isavuconazonium sulfate salt of the present invention (form GL-1) and described herein is stable at 3 months under the storage conditions specified herein.

[0092] Thus, in one embodiment, the present invention provides stable crystalline isavuconazonium sulfate (Form GL-1), having less than about 0.2% w / w of any of the impurities selected from compounds of formula IV, VI, VII, VIII, IX, X, or XI as determined by HPLC.

[0093] In one embodiment, the present invention provides stable crystalline isavuconazonium sulfate (Form GL-1) having an amount of about 0.03% to about 0.2% w / w of any impurity selected from compounds of formula IV, VI, VII, VIII, IX, X, or XI as determined by HPLC.

[0094] Thus, in one embodiment, the present invention provides stable crystalline isavuconazonium sulfate (Form GL-1) having any impurity selected from compounds of formula IV, VI, VII, VIII, IX, X, or XI in an amount of about 0.03% to about 0.2% w / w as measured by HPLC at 3 months under the storage conditions specified herein.

[0095] The term "about" when used with respect to the content of impurities typically refers to a range within 1%, more typically within 0.5% of the indicated value or range. The allowable variation encompassed by the term "about" depends on the system under test and what is understandable to one of ordinary skill in the art.

[0096] The isavuconazonium sulfate used in step (a) of the process for preparing the crystalline isavuconazonium sulfate (form GL-1) of the present invention disclosed herein can be prepared according to the process disclosed in IN201821035971, the process comprising: (i) in the presence of methanol, a compound of formula II:

[0097] [ka]

[0098] The compound of formula III:

[0099] [ka]

[0100] to react with a compound of formula IV:

[0101] [ka]

[0102] obtaining a reaction mixture comprising isavuconazole, (j) reacting isavuconazole, a compound of formula IV obtained from the above reaction mixture, with a compound of formula V:

[0103] [ka]

[0104] to obtain N-Boc isavuconazonium iodide; k) converting N-Boc isavuconazonium iodide to N-Boc isavuconazonium chloride, which is a compound of formula XI; l) converting N-Boc isavuconazonium chloride to isavuconazonium sulfate.

[0105] The present invention also provides a pharmaceutical composition comprising crystalline isavuconazonium sulfate (form GL-1) and at least one pharma- ceutically acceptable excipient.

[0106] The pharmaceutical compositions of the present invention can be administered orally to a subject in need thereof, for example in the form of tablets, capsules, granules, or powders, or can be administered parenterally in the form of an injection, or intranasally, or in the form of a transdermal patch.

[0107] In one embodiment, the pharmaceutical composition of the present invention may be orally administered to a subject in need thereof in a dosage form selected from a tablet or a capsule.

[0108] In another embodiment, the pharmaceutical compositions of the present invention can be administered parenterally to a subject in need thereof in the form of an injection.

[0109] In an exemplary embodiment, the pharmaceutical composition comprises a therapeutically effective amount of crystalline isavuconazonium sulfate (form GL-1) as described herein. As used herein, the term "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a condition, disorder, or symptom, is sufficient to effect such treatment. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, physical condition, and responsiveness of the mammal being treated.

[0110] As used herein, the term "administering" refers to providing a therapeutically effective amount of an active ingredient to a particular site within a subject, resulting in a therapeutically effective blood concentration of the active ingredient at the particular site. This can be accomplished, for example, by topical, oral, local, or systemic administration of the active ingredient to the subject.

[0111] As used herein, the term "pharmaceutical acceptable excipient" refers to a substance that exhibits no significant therapeutic or pharmacological activity at a particular dose of the pharmaceutical agent and that is added to a pharmaceutical composition in addition to an active ingredient (API).

[0112] The pharma- ceutically acceptable excipients used in the pharmaceutical compositions of the present invention can be selected from the group consisting of carriers, fillers, diluents, lubricants, sweeteners, stabilizers, solubilizers, antioxidants and preservatives, flavoring agents, binders, coloring agents, osmotic agents, buffers, surfactants, disintegrants, granulating agents, coating materials, and combinations thereof.

[0113] As mentioned above, isavuconazonium sulfate is sold under the trade name CRESEMBA® in capsules containing 186 mg of isavuconazonium sulfate and as an intravenous (infusion) powder containing 372 mg of isavuconazonium sulfate.

[0114] Therefore, it will be readily apparent to those skilled in the art how to formulate the crystalline isavuconazonium sulfate of the present invention into an appropriate dosage form depending on the dose of the pharmaceutical agent to be administered.

[0115] In other embodiments, the present invention also relates to a method of treating a fungal infection, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline isavuconazonium sulfate (form GL-1) as disclosed herein.

[0116] As used herein, the term "subject in need thereof" refers to a mammal suffering from or at risk of developing a fungal infection. The subject may be diagnosed as suffering from a fungal infection as described herein. Alternatively, the subject may exhibit one or more symptoms of a fungal infection.

[0117] The term "subject" or "patient" as used herein refers to a mammal, preferably a human.

[0118] Fungal infections can be topical and mucosal fungal infections caused by Candida, Trichophyton, or Microsporum, among other genera.

[0119] In one embodiment, the crystalline isavuconazonium sulfate (form GL-1) of the present invention or a pharmaceutical composition comprising said crystalline isavuconazonium sulfate (form GL-1) disclosed herein is provided for use in the treatment of a fungal infection selected from mucormycosis or invasive aspergillosis.

[0120] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention and should not be construed as limiting the scope of the invention. EXAMPLES

[0121] General method 1.HPLC method: To detect the chemical purity, high performance liquid chromatography (HPLC) was performed under the following conditions:

[0122] Column: Xterra MS C18, 150 x 4.6 mm, 3.5μ; Column temperature: 45°C; Mobile phase: Mobile phase A = 0.1% perchloric acid in water; Mobile phase B = methanol

[0123] [Table 1]

[0124] Diluent: methanol: 0.3% sodium bisulfate (70:30 v / v); flow rate: 1.0 mL / min, detection: 260 nm; injection volume: 20 μL

[0125] 2. Infrared Spectroscopy (Instrument Settings): Instrument name: Perkin Elmer; Model: Spectrum 1; Method: 300-400 mg of KBr, previously dried at 200 °C and cooled, was placed in a mortar and ground to a fine powder. 1.0 mg-2.0 mg of test sample was added, mixed well, and ground to a fine powder. A small amount of powder was taken and a thin translucent pellet was made from the powder. The IR spectrum of the pellet was measured at 4000 cm vs. air. -1 ~650cm -1 It was recorded up to.

[0126] 3. X-ray Powder Diffraction (XRPD) (Instrument Settings): The measurements were carried out on a Philips X-ray diffractometer model XPERT-PRO (PANalytical) with a Cu lamp and a detector: X'celerator [1] under the following conditions: type and wavelength of X-ray radiation: K-α 11.54060 [Å], K-α 21.5444 [Å]; Pre FIX module programmable divergence slit and anti-scatter slit (offset 0.00°); generator settings: 40 mA / 45 kV, tube current 40 mAmp, time per step: 50 s, step size: 0.0167, peak width 2.00, start angle ( o Measurements were performed with a chromaticity of 1.0 nm; end angle: 50.0; scan type: continuous; and measurement at 25° C. The XRPD instrument was calibrated using the NIST SRM 6-40C silicon standard and NIST SRM 1976 Alumina.

[0127] Sample preparation: Using the backloading technique, take a sufficient amount of sample to fill the sample holder. The sample holder is then loaded into the X-ray optical path and scanned using the parameters described above. The resulting powder X-ray diffraction profile is integrated using X'Pert HighScore Plus Software.

[0128] 4. Thermogravimetric analysis (instrument settings): TGA thermograms were recorded using a TGA-Q500 (Waters). Approximately 5–10 mg of sample was collected in a sample holder and loaded into the furnace. The sample was heated to 250 °C at a ramp rate of 10 °C / min, and the thermograms were integrated using Universal V4.5A software.

[0129] 5. Percentage of crystallinity (instrument settings): The crystallinity percentage analysis was performed by inserting the measurement file xrdml (X-ray powder diffraction measurement data) into X'Pert HighScore Plus Software. A manual range was set at the start position [°2θ] and clipped. A high grain size and a "0" bending factor were selected by the automatic background measurement. This method was repeated to define the background such that the non-crystalline humps were incorporated into the background. The minimum intensity from the scattering values ​​was used as an input for the constant background in the scan statistics. The crystallinity [%] value was then calculated.

[0130] PANalytical Highscore uses a crystallinity algorithm as follows. Crystallinity [%]=100×Σ Inet. / (Σ Itotal.-Σ Iconstant background); where "Inet" refers to the area of ​​the crystalline peak, "Itotal" refers to the combined area of ​​the crystalline and amorphous peaks, and "Iconstant background" refers to the amorphous area in the diffractogram.

[0131] Example 1 Synthesis of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate monosulfate salt (isavuconazonium sulfate salt). 4H-1,2,4-Triazolium,1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-[[[[3-[[[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]acetyl]oxy]methyl]-2-pyridinyl]methylamino]carbonyl]oxy]ethyl] chloride (Compound XI, 125 gm) was suspended in isopropyl acetate (1875 mL). The reaction mass was cooled to 10°C-20°C and to this, 8-12% hydrochloric acid in ethyl acetate (625 mL) was added. The reaction mixture was stirred at 10-20°C for 3 hours. On completion of reaction, Celite was added and stirred for 10 minutes. The product was filtered and washed with ethyl acetate. To the wet cake, water and methylene dichloride were added, stirred and filtered. The aqueous layer was passed through a sulfate-containing anion exchange resin. The isavuconazonium sulfate-containing aqueous solution from the resin column was distilled under vacuum at less than 30° C. to obtain an oily residue. Purity: 94.53%. Acetonitrile (2500 mL) and water (62.5 mL) were added to the residue and stirred for 12 hours. The precipitated product was filtered to obtain (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate monosulfate salt.

[0132] Purity as determined by the above HPLC method: 99.5%. The content of each of the impurities of the compounds of formulae IV, VI, VII, VIII, IX, X, and XI as determined by HPLC is less than 0.2% w / w.

[0133] Example 2 Synthesis of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate monosulfate salt (isavuconazonium sulfate salt). 4H-1,2,4-Triazolium, 1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-[[[[3-[[[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]acetyl]oxy]methyl]-2-pyridinyl]methylamino]carbonyl]oxy]ethyl] chloride (Compound XI, 10 gm) was suspended in isopropyl acetate (150 ml). The reaction mass was cooled to 10-20°C and to this was added 8-12% hydrochloric acid in ethyl acetate (50 mL). The reaction mass was stirred at 10-20°C for 3 hours. On completion, Celite was added and stirred for 10 minutes. The product was filtered and washed with ethyl acetate. Water and methylene dichloride were added to the wet cake, stirred and filtered. The aqueous layer was passed through a sulfate-containing anion exchange resin while washing with water. The aqueous solution from the sulfate-containing anion exchange resin was passed through a polyethersulfone-based nanofiltration membrane (PES) having a diameter of 150-300 Daltons to achieve an aqueous layer concentration of more than 35%. The purity of the aqueous layer was 96.5%. Acetonitrile (200 mL) was added to the aqueous layer and stirred for 12 hours. The precipitated product was filtered to obtain (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate sulfonium salt (5 gm).

[0134] Purity as determined by the above HPLC method:>99%. The content of each of the impurities of the compounds of formulae IV, VI, VII, VIII, IX, X, and XI as determined by HPLC is less than 0.2% w / w.

[0135] Example 3 Synthesis of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate monosulfate salt (isavuconazonium sulfate salt). 4H-1,2,4-Triazolium,1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-[[[[3-[[[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]acetyl]oxy]methyl]-2-pyridinyl]methylamino]carbonyl]oxy]ethyl]chloride (compound XI, 400 gm) was suspended in a solution of water (2000 mL) and concentrated HCl (366 gm). The reaction mixture was stirred at 20-30° C. for 12 hours. To the reaction mixture, methylene dichloride (4000 mL) was added and stirred. The layers were separated. The aqueous layer containing the product was passed through a sulfate-containing anion exchange resin. The aqueous solution from the sulfate-containing anion exchange resin was passed through a nanofilter polyethersulfone (PES) having a diameter of 150-300 (daltons). The water content was reduced to about 1-2 volumes of the retentate, to which acetonitrile (25 volumes) was added relative to the retentate volume and stirred for 5-6 hours. The precipitated product was filtered and dried to give 172 gm of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate sulfonium salt. Purity: 99.76% as determined by the above HPLC method. The content of each of the impurities of the compounds of formulae IV, VI, VII, VIII, IX, X, and XI is less than 0.2% w / w as determined by HPLC.

[0136] The crystalline isavuconazonium sulfate obtained according to Example 3 was analyzed by powder X-ray diffraction, IR spectroscopy, and TG test, and the results are shown in Figures 1, 2, and 3, respectively.

[0137] Example 4 Synthesis of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate chloride (Compound XI). 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile (compound IV, 880 gm) was suspended in a mixture of methyl isobutyl ketone (3520 mL) and acetonitrile (1760 mL) to obtain a reaction mass. To this reaction mass, (2-{[(1-chloroethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate (compound V, 1086 gm) and sodium iodide (361.7 gm) were added. The reaction mass was heated to a temperature of 35°C-45°C and maintained at a temperature of 35°C-45°C for about 8-9 hours. The reaction mass was filtered and the filtrate was distilled under vacuum. The residue obtained was dissolved in methanol (7920 ml), 7920 ml of SA10A (chloride) resin was added and the reaction mass was stirred for a period of about 1.0 hour. The reaction mass was filtered and washed with methanol. To the filtrate, chloride resin (5280 mL) was added, stirred for a period of about 1 hour and filtered. To the filtrate, water and toluene were added. The layers were separated, the aqueous layer was washed with toluene and the aqueous layer was extracted with methylene dichloride (MDC). Thereafter, the MDC layer was washed with 2% hydrochloric acid solution and 10% sodium chloride solution, the MDC layer was distilled and the residue obtained was dissolved in ethyl acetate (2640 ml) and the solution was added to pre-cooled n-heptane (7040 mL) at -5-5°C. The precipitated product was filtered and dried under vacuum at 45-50°C to obtain 1188 g of the title product. Purity as determined by above HPLC method: 98.91%.

[0138] Example 5 Stability testing of crystalline isavuconazonium sulfate: Comparative stability data was generated for crystalline isavuconazonium sulfate (form GL-1) and the amorphous form of isavuconazonium sulfate (prepared as described in Comparative Example 1) stored at temperatures of -20°C and 2°C to 8°C for 3 months (i.e., 12 weeks). In particular, appropriate amounts of crystalline isavuconazonium sulfate (form GL-1) obtained according to Example 3 and the amorphous form of isavuconazonium sulfate of Comparative Example 1 were taken and packed into transparent polyethylene bags. The bags were sealed under vacuum, then sealed in black LDPE (low density polyethylene) bags, and further maintained in triple laminated aluminum bags sealed on three sides. The fourth side of the bags was then sealed under vacuum, maintained in HDPE (high density polyethylene) containers, and stored at -20°C and 2°C to 8°C for 3 months (i.e., 12 weeks). Both materials were analyzed by the HPLC method described above after 3 months of storage.

[0139] The stability data for crystalline isavuconazonium sulfate (form GL-1) compared to amorphous isavuconazonium sulfate is shown in Table 1 below.

[0140] [Table 2]

[0141] The stability data presented in Table 1 above demonstrates that the stability of crystalline isavuconazonium sulfate (form GL-1) is maintained for up to at least three months when stored under the storage conditions specified above. Form GL-1 is found to be more stable over a three month period compared to the amorphous form of isavuconazonium sulfate.

[0142] (Reference Example 1) Synthesis of 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile (Compound IV). To (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butane-thioamide (compound II, 50 gm) in isopropyl alcohol (II, 150 mL) was added 4-(bromoacetyl)benzonitrile (compound III, 35.9 gm) to obtain reaction mass. The reaction mass was heated to 40-50°C. On completion of reaction, the solvent was distilled and ethyl acetate and water were added to the reaction mass. The pH of the reaction mass was adjusted to 7.0-8.0 by aqueous solution of sodium bicarbonate. The layers were separated and the organic layer was washed with saturated sodium chloride solution. The organic layer was distilled to obtain an oily mass. To the oily mass, isopropyl alcohol was added and the solution was heated at a temperature of 55°C-65°C and water was added. The reaction mass was cooled to 15°C-25°C and stirred for 4 hours. The solid obtained was filtered and washed with a mixture of isopropyl alcohol and water to obtain 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile (54 gm). Purity by HPLC: 99.96%.

[0143] (Reference Example 2) Synthesis of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate chloride (Compound XI). 4-{2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl}benzonitrile (compound IV, 100 g) of Reference Example 1 was suspended in acetonitrile (750 mL) and (2-{[(1-chloroethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate (compound V, 128 gm) was added to obtain a reaction mass. The reaction mass was heated at a temperature of 55° C.-60° C. A solution of sodium iodide (41.11 gm) in acetonitrile (650 mL) was added and the reaction mass was maintained at a temperature of about 55° C.-60° C. for about 8-10 hours. The reaction mass was filtered and the filtrate was distilled completely under vacuum. The residue obtained was dissolved in methanol (600 mL) and Diaion® SA10A (chloride) (900 mL) resin was added and the reaction mass was stirred for 1 hour. The reaction mass was filtered and washed with methanol to isolate the product. Purity by HPLC: 89.56%.

[0144] To the solution obtained above, water and toluene were added. The layers were separated, the aqueous layer was washed with toluene, and the aqueous layer was extracted with methylene dichloride (MDC). The MDC layer was distilled, the residue was dissolved in ethyl acetate (400 mL), and n-heptane (1000 mL) was added thereto. The product was precipitated at a temperature of -5°C to 0°C, filtered, and dried under vacuum at a temperature of 45 to 50°C to obtain 130 g of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-(tert-butoxycarbonyl)-N-methylglycinate chloride. Purity by HPLC: 97.81%.

[0145] Comparative Example 1 Synthesis of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate monosulfate salt (amorphous form). In isopropyl acetate (compound XI, 1800 mL) was suspended 4H-1,2,4-triazolium,1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-[[[[3-[[[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]acetyl]oxy]methyl]-2-pyridinyl]methylamino]carbonyl]oxy]ethyl] chloride (120 gm). The reaction mass was cooled to 10-20°C and to this, 8-12% hydrochloric acid in ethyl acetate (600 mL) was added. The reaction mixture was stirred at 10-20°C for 3 hours. On completion of reaction, the product was filtered and washed with ethyl acetate. The wet cake was dissolved in 360 mL water and the aqueous layer was washed with methylene dichloride. The aqueous layer was passed through a sulfate-containing anion exchange resin. The isavuconazonium sulfate-containing aqueous solution from the resin column was washed with 10% n-butanol-methylene dichloride (1200 mL). The resulting aqueous layer was washed with methylene dichloride and cyclohexane. The aqueous layer was then freeze-dried at a temperature of -80°C to obtain 68 gm of (2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl-N-methylglycinate monosulfate salt in amorphous form. Purity 97.29%.

Claims

1. XRPD pattern with peaks at 6.45, 7.25, 15.98, 16.87, 17.25, and 20.93±0.2° 2θ; -1 and a thermogravimetric analysis (TGA) thermogram determined over a temperature range of 0° C. to 250° C. at a heating rate of 10° C. / min, exhibiting a weight loss of about 6.56% up to 150° C. A crystalline form of isavuconazonium sulfate (Form GL-1), characterized by one or more data selected from the group consisting of an IR (infrared) spectrum having a major band at

2. 2. The crystalline form of isavuconazonium sulfate of claim 1 (Form GL-1), wherein the crystalline form is characterized by an XRPD pattern having one or more additional peaks at 12.5, 17.83, 21.99, and 22.56±0.2 degrees 2θ.

3. A crystalline form of isavuconazonium sulfate (Form GL-1), characterized by an XRPD pattern substantially as shown in FIG.

4. A crystalline form of isavuconazonium sulfate (form GL-1) characterized by its IR spectrum as shown in FIG.

2.

5. A crystalline form of isavuconazonium sulfate (Form GL-1), characterized by a TGA thermogram substantially as shown in FIG.

6. 6. The crystalline form of isavuconazonium sulfate according to any one of claims 1 to 5 (form GL-1), wherein said crystalline form has a crystallinity of at least 30%.

7. 6. The crystalline form of isavuconazonium sulfate according to any one of claims 1 to 5, wherein the amorphous content of said crystalline form of isavuconazonium sulfate is 70% or less (form GL-1).

8. The crystalline form of isavuconazonium sulfate according to any one of claims 1 to 7, wherein the crystalline form comprises epimer I and epimer II in a 1:1 ratio, as represented by the following structure (form GL-1). 【Chemistry 1】

9. 9. The crystalline form of isavuconazonium sulfate of any one of claims 1 to 8 (Form GL-1), wherein the crystalline form contains an impurity selected from compounds of formula IV, VI, VII, VIII, IX, X, or XI, represented below by the following chemical structures, in an amount of less than about 0.2% w / w: 【Chemistry 2A】 【Chemistry 2B】

10. (a) providing a reaction mixture comprising isavuconazonium sulfate and a solvent system comprising a nitrile solvent and water; (b) stirring the reaction mixture of step (a) to precipitate isavuconazonium sulfate; (c) isolating the crystalline form of isavuconazonium sulfate obtained in step (b); 10. A process for preparing the crystalline form of isavuconazonium sulfate (form GL-1) according to any one of claims 1 to 9, comprising:

11. 11. The process of claim 10, wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, and isobutyronitrile.

12. 12. The process according to claim 10 or 11, wherein the nitrile solvent is acetonitrile.

13. 13. The method of any one of claims 10 to 12, wherein step (a) is carried out at a temperature between about 0°C and about 25°C.

14. 14. A crystalline form of isavuconazonium sulfate (form GL-1) obtained by the process according to any one of claims 10 to 13, wherein the purity of said crystalline form is at least 99%.

15. 10. A pharmaceutical composition comprising the crystalline form of isavuconazonium sulfate (form GL-1) according to any one of claims 1 to 9 and at least one pharma- ceutically acceptable excipient.

16. 10. Use of a crystalline form of isavuconazonium sulfate (form GL-1) according to any one of claims 1 to 9 for the treatment of a fungal infection selected from mucormycosis or invasive aspergillosis.

17. 10. A method of treating a fungal infection that is mucormycosis or invasive aspergillosis, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline isavuconazonium sulfate (form GL-1) according to any one of claims 1 to 9.

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