FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Oteseconazole and Oteseconazole: Piperazine, in embodiments crystalline polymorphs of Oteseconazole and crystalline Oteseconazole: Piperazine, processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0002] Oteseconazole, (2R)-2-(2,4-Difluorophenyl)- 1 , 1 -difluoro-3 -( 1H- 1 ,2,3 ,4-tetrazol- 1 - yl)-l-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propa n-2-ol, has the following chemical structure:

[0003] Oteseconazole is an oral antifungal product candidate for the treatment of acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC), and may also have therapeutic potential in the treatment of other fungal conditions such as tinea pedis, onychomycosis, candidiasis, meningitis (e.g., cryptococcal meningitis), or mucormycosis.

[0004] The compound is described in U.S. Patent No. 8,236,962. Oteseconazole polymorphs are described in U.S. Patent Nos. 9,840,492; 10,370,353; 10,414,751 and 10,676,459.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state ( ¹³ C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. [0006] Different polymorphs, salts or Co-crystal and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of polymorphs, different salts/ Co-crystal and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of polymorphs, different salts/ Co-crystals and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different polymorphs, salts/Co-crystal and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Oteseconazole.

SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine, processes for preparation thereof, and pharmaceutical compositions thereof.

[0009] In embodiments, the present disclosure provides crystalline form of Oteseconazole designated as Form 01 and crystalline Oteseconazole: Piperazine Form PCC1.

[0010] The present disclosure also relates to any one or combination of the described crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine for use in preparing other solid state forms of Oteseconazole, Oteseconazole salts or crystalline Oteseconazole: Piperazine and their solid state forms.

[0011] The present disclosure also provides uses of any one or combination of the said solid state form of Oteseconazole and crystalline Oteseconazole: Piperazine in the preparation of other solid state forms of Oteseconazole, crystalline Oteseconazole: Piperazine or salts thereof.

[0012] The present disclosure provides crystalline polymorph of Oteseconazole and- crystalline Oteseconazole: Piperazine and solid state forms thereof for use in medicine, including for the treatment of acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC), or tinea pedis, onychomycosis, candidiasis, meningitis (e.g., cryptococcal meningitis), or mucormycosis. Optionally, the present disclosure provides crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine and solid state forms thereof for use in medicine, including for the treatment of candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and preferably RVVC,

[0013] The present disclosure also encompasses the use of crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine or solid state form thereof of the present disclosure for the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC) , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g., cryptococcal meningitis), or mucormycosis. Optionally, the present disclosure provides the use of crystalline polymorphs of Oteseconazole and crystalline Oteseconazole: Piperazine and solid state forms thereof for the preparation of pharmaceutical compositions and/or formulation for the treatment of candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and preferably RVVC

[0014] In another embodiment, the present disclosure encompasses crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine or the described solid state form thereof for use in the preparation of pharmaceutical compositions and/or formulations, optionally for the treatment of acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC) , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g., cryptococcal meningitis), or mucormycosis. Optionally, the present disclosure provides crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine and solid state forms thereof for use in the preparation of pharmaceutical compositions and/or formulations for the treatment of candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and preferably RVVC.

[0015] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorph of Oteseconazole and/or- crystalline Oteseconazole:

Piperazine or the described solid state forms thereof according to the present disclosure.

[0016] In yet another embodiment, the present disclosure encompasses pharmaceutical formulations including crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine or the described solid state forms thereof and at least one pharmaceutically acceptable excipient

[0017] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine or the described solid state forms thereof with at least one pharmaceutically acceptable excipient.

[0018] The crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine may be used as medicaments, such as for the treatment of acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC) , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g., cryptococcal meningitis), or mucormycosis. Optionally, the crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine may be used as medicaments for the treatment of candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and preferably RVVC.

[0019] The present disclosure also provides methods of treating acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC), , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g. cryptococcal meningitis), or mucormycosis; preferably candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and more preferably RVVC, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from acute Vulvovaginal Candidiasis or RVVC, , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g. cryptococcal meningitis), or mucormycosis; preferably candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and more preferably RVVC, or otherwise in need of the treatment.

[0020] The present disclosure also provides uses of crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating, e.g., acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC) , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g., cryptococcal meningitis), or mucormycosis. Optionally, the present disclosure also provides uses of crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and more preferably RVVC.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Oteseconazole Form 01.

[0022] Figure 2 shows a characteristics X-ray powder diffraction pattern (XRPD) of crystalline Oteseconazole: Piperazine Form PCC1.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0023] The present disclosure encompasses solid state form of Oteseconazole and/or crystalline Oteseconazole: Piperazine, including crystalline polymorph of Oteseconazole and/or crystalline Oteseconazole: Piperazine, processes for preparation thereof, and pharmaceutical compositions thereof.

[0024] The disclosure also relates to conversion of the solid state form of Oteseconazole and/or crystalline Oteseconazole: Piperazine or the described forms thereof to other forms thereof, Oteseconazole or salts or co-crystal and solid state forms thereof.

[0025] Solid state properties of Oteseconazole and Oteseconazole: Piperazine and crystalline polymorphs thereof can be influenced by controlling the conditions under which Oteseconazole and Oteseconazole: Piperazine and crystalline polymorphs thereof are obtained in solid form. [0026] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Oteseconazole and Oteseconazole: Piperazine described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine, respectively. In some embodiments of the disclosure, the described crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Oteseconazole and crystalline Oteseconazole: Piperazine, respectively.

[0027] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0028] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Oteseconazole referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Oteseconazole characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0029] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline form of Oteseconazole and crystalline Oteseconazole: Piperazine relates to a crystalline form of Oteseconazole and crystalline Oteseconazole: Piperazine which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.

[0030] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0031] "Co-Crystal" or "Co-crystal" as used herein is defined as a crystalline material including two or more molecules in the same crystalline lattice and associated by non-ionic and non-covalent bonds. Co-crystals may comprise a pharmaceutical agent and at least one co-crystal former and may themselves be solvated or unsolvated. In some embodiments, the co-crystal includes two molecules which are in natural (i.e., non-ionized) state.

[0032] As used herein, crystalline Oteseconazole: Piperazine is a distinct molecular species. Crystalline Oteseconazole: Piperazine may be a co-crystal of Oteseconazole and Piperazine. [0033] In an embodiment, the molar ratio between the active pharmaceutical ingredient (Oteseconazole) and the coformer (Piperazine) is between 1: 1.5 and 1.5: 0.5, preferably between 1: 1.25 and 1.25: 0.5, in other embodiments about 1:0.5.

[0034] As used herein, the term "isolated" in reference to crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure corresponds to a crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine that is physically separated from the reaction mixture in which it is formed.

[0035] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are measured using CuK a radiation, l = 1.5418 A, typically at a temperature of 25 ± 3°C.

[0036] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0037] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added. [0038] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0039] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0040] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0041] The present disclosure includes a crystalline polymorph of Oteseconazole, designated Form 01. The crystalline Form 01 of Oteseconazole may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 11.0, 12.8, 17.3, 17.7 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0042] Crystalline Form 01 of Oteseconazole may be further characterized by an X-ray powder diffraction pattern having peaks at 11.0, 12.8, 17.3, 17.7 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 14.9, 18.9, 21.5, 23.2 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0043] Alternatively, crystalline Form 01 of Oteseconazole, which is characterized by an XRPD pattern having peaks at 11.0, 12.8, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2-theta; and one, two, or three additional peaks at 16.6, 23.2, and 28.0 degrees 2-theta ± 0.2 degrees 2- theta. Thus, crystalline form 01 of Oteseconazole may be characterized by an XRPD pattern having peaks at: 11.0, 12.8, 16.6, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2-theta; or an XRPD pattern having peaks at: 11.0, 12.8, 17.3, 23.2 and 26.7 degrees 2-theta ± 0.2 degrees 2- theta; or an XRPD pattern having peaks at: 11.0, 12.8, 17.3, 26.7 and 28.0 degrees 2-theta ± 0.2 degrees 2-theta, or an XRPD pattern having peaks at: 11.0, 12.8, 16.6, 17.3, 23.2 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta; or XRPD pattern having peaks at 11.0, 12.8, 16.6, 17.3, 23.2, 26.7, and 28.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0044] In any embodiment of the disclosure herein, crystalline Form 01 of Oteseconazole may be characterized by an X-ray powder diffraction pattern as defined as described according to any of the definitions here, and further characterized by: an absence of a peak at 19.9 degrees 2- theta ± 0.2 degrees 2-theta; or an absence of a peak at 20.8 degrees 2-theta ± 0.2 degrees 2-theta; or an absence of peaks at 19.9 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0045] In an alternative embodiment of the disclosure herein, crystalline Form 01 of Oteseconazole which is characterized by an XRPD pattern having peaks at: 11.0, 12.8, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2-theta; and in addition: an absence of a peak at 19.9 degrees 2-theta ± 0.2 degrees 2-theta, or an absence of a peak at 20.8 degrees 2-theta ± 0.2 degrees 2- theta; or an absence of peaks at 19.9 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form 01 of Oteseconazole according to this embodiment may be further characterized by an XRPD having one, two, or three additional peaks at 16.6, 23.2, and 28.0 degrees 2-theta ± 0.2 degrees 2-theta. For example, crystalline Form 01 of Oteseconazole may be characterized by an XRPD pattern having peaks at: 11.0, 12.8, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2-theta and an absence of a peak at 19.9 degrees 2-theta ± 0.2 degrees 2-theta (optionally with one, two, or three additional peaks at 16.6, 23.2, and 28.0); or an XRPD pattern having peaks at: 11.0,

12.8, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2-theta and an absence of a peak at 20.8 degrees 2-theta ± 0.2 degrees 2-theta (optionally with one, two, or three additional peaks at 16.6, 23.2, and 28.0); or an XRPD pattern having peaks at: 11.0, 12.8, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2-theta and an absence of peaks at 19.9 and 20.8 degrees 2-theta ± 0.2 degrees 2- theta (optionally with one, two, or three additional peaks at 16.6, 23.2, and 28.0).

[0046] Oteseconazole Form 01 as described in any embodiment herein may be anhydrous.

In embodiments, Oteseconazole Form 01 contains 0.5% (w/w) or less of water and organic solvents.

[0047] In one embodiment of the present disclosure, crystalline Form 01 of Oteseconazole is isolated.

[0048] Crystalline Form 01 of Oteseconazole may alternatively be characterized by an XRPD pattern having peaks at 11.0, 12.8, 14.9, 17.3, 17.7, 18.9, 21.5, 23.2, 24.5 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0049] Crystalline Oteseconazole Form 01 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., XRPD pattern having peaks at 11.0, 12.8, 17.3, 17.7 and 26.7 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0050] The above crystalline polymorph can be used to prepare other crystalline polymorphs of Oteseconazole, Oteseconazole salts and their solid state forms.

[0051] In another embodiment of the present disclosure, crystalline Oteseconazole Form 01 is polymorphically pure.

[0052] In any aspect or embodiment of the present disclosure, the crystalline Oteseconazole Form 01 described herein may be substantially free of any other solid state forms of Oteseconazole. In embodiments, crystalline Oteseconazole Form 01 according to any aspect or embodiment of the present invention contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% (w/w) of any other forms of Oteseconazole as measured, for example, by XRPD.

[0053] The above Oteseconazole Form 01 may be prepared by a process comprising crystallization of Oteseconazole in a solvent selected from diisopropyl ether or alcohol solvent.

In any embodiment of this process, the solvent is preferably an alcohol preferably a Ci- ₆ alcohol, more preferably a C3-6 alcohol, and most preferably a C4-6 alcohol. In any embodiment of this process, the solvent may be diisopropyl ether, or an alcohol selected from: tert-butanol, amyl alcohol, iso-amyl alcohol and iso-butanol. In any embodiment of this process, the solvent is preferably isobutanol. The process may comprise stirring a solution or suspension, preferably a solution, of Oteseconazole in the solvent for a sufficient time to precipitate Oteseconazole Form 01. The solvent may be used in an amount of 0.5-10 ml, 1-5 ml, 1-3 ml, or about 2 ml, per gram of Oteseconazole. In any embodiment, the process may be carried out by dissolution of the Oteseconazole in /50-butanol, optionally with stirring. In embodiments, 0.5-10 vol of i.so- butanol, in some embodiments 1-5 vol, in other embodiments 1-3 vol, and in yet other embodiments about 2 vol of iso-butanol may be used to dissolve Oteseconazole.

[0054] In any embodiment of this process, the mixture of Oteseconazole in the solvent (preferably as a solution) may be held at room temperature, in embodiments at about 20°C to about 25°C, in some embodiments at 25°C, for a suitable time to allow precipitation to occur. Typically, the mixture is held, optionally with stirring, for a time period of about several minutes to about 24 hours until precipitation is observed.

[0055] Isolation of the said crystalline form may be done for example by centrifuge or filtering the suspension and optionally drying. Drying may be done by nitrogen or air or under vacuum. In embodiments, drying is performed at a temperature of about 40-60°C, in embodiments about 40-50°C, and in other embodiments about 45°C, in some cases under vacuum (in embodiments a reduced pressure of: 1-200 mbar, in other embodiments 1-100 mbar, in some embodiments 1-50 mbar, and in other embodiments 1-20 mbar or about 10 mbar).

[0056] Alternatively, the present disclosure further includes a process for the preparation of Oteseconazole Form 01, which comprises a sol vent/ anti solvent crystallization. In any embodiment of this process, Oteseconazole Form 01 may be prepared by a solvent/anti solvent crystallisation wherein the solvent may be an alcohol, or an ester, wherein the alcohol amyl alcohol, isobutanol or cyclohexanol. Preferably the ester is a C2-6 ester, more preferably ethyl formate, methyl formate, isobutyl acetate, or ethyl acetate. The process may comprise: a) providing a solution of Oteseconazole in a solvent selected from: an alcohol, or an ester, optionally wherein the solution is heated; b) optionally filtering the solution; c) combining the solution with an antisolvent; d) optionally isolating form 01 of Oteseconazole and; e) optionally drying.

[0057] Optionally, Oteseconazole used in step a) can be prepared by dissolving Oteseconazole in the alcohol, or an ester. The alcohol solvent is amyl alcohol, iso-butanol or cyclohexanol. In any embodiment of this process, the ester solvent is preferably a C2-6 ester, preferably selected from iso-butyl acetate, ethyl acetate, ethyl formate and methyl formate, and more preferably ethyl formate or methyl formate, particularly ethyl formate. In any embodiment of this process, the solvent is preferably amyl alcohol, isobutanol, cyclohexanol, or ethyl formate. In any embodiment of this process, the solution in step (a) may be at a temperature of about 30 to about 100°C, about 35 to about 70°C, about 40-60°C, or about 50°C. The solution in step (a) may be prepared by combining Oteseconazole with a heated solvent which is heated to a temperature as described above, or the Oteseconazole may be combined with the solvent, and the mixture heated to the above described temperature. The mixture in step (a) may optionally be stirred. The mixture may be optionally filtered to remove insoluble materials (step (b)).

[0058] In any embodiment of this process, the solvent is used in an amount of: about 1 to about 20 ml, about 2 to about 15 ml, about 2 to about 12 ml , per gram of Oteseconazole. In embodiments, the solvent is preferably amyl alcohol, isobutanol, cyclohexanol, or ethyl formate. In a preferred embodiment according to this process, the solvent may be an alcohol selected from amyl alcohol, isobutanol or cyclohexanol, wherein the solvent is used in an amount of about 1-20 vol, about 2-15 vol, in embodiments about 2-10 vol. In other embodiments, the solvent is used in an amount of about 2 to about 5 vol, or about 3 vol, particularly when the solvent is amyl- alcohol, iso-butyl acetate or ethyl acetate. In other embodiments, the solvent is isobutanol, in an amount of about 1 to about 8 vol, about 2 to about 6 vol, about 3 to about 5 vol, or preferably about 4 vol. In another embodiment, the solvent is cyclohexanol, in an amount of about 1 to about 20 vol, about 2 to about 15 vol, about 5 to about 12 vol, or about 10 vol. In yet another embodiment, the solvent is amyl alcohol, in an amount of about 1 to about 7, about 1 to about 6, about 2 to about 4, or about 3 vol. Preferably, in any embodiment of the process, the mixture in step (a) is at a temperature of about 35°C to about 55°C, or about 40°C to about 50°C.

Preferably, step (b) is conducted at the elevated temperature.

[0059] In any embodiment of this process, step (c) comprises combining the solution obtained in step (a) or step (b) with an antisolvent which is an alkane, preferably a C5-10 alkane, more preferably a C5-8 alkane or a mixture of such alkanes. The alkane may be straight chain, branched, or cyclic or may be a mixture of one or more such alkanes. In any embodiment of this process, the alkane anti solvent is selected from n-heptane, hexane, pentane, octane, cyclohexane and petroleum-ether, and preferably n-heptane or octane. In embodiments, the alkane is used in an amount of about 5 to about 50 vol, about 8 to about 40 vol, about 10 to about 30 vol. The alkane may be added dropwise to the solution of Oteseconazole in the solvent, for example, over a period of about 5 to about 30 minutes, about 5 to about 20 minutes, or within about 10 minutes. In embodiments, the suspension is cooled to temperature of about -25°C to about 25°C, about - 20°C to about 25°C.

[0060] Alternatively, in any embodiment of this process, step (c) may comprise adding the solution of Oteseconazole in the solvent to the antisolvent (i.e., reverse addition). Preferably the reverse addition comprises adding Oteseconazole solution (preferably wherein the Oteseconazole is in a solution with amyl alcohol), dropwise to the antisolvent. The addition may be carried out over a period of about 5 to about 30 minutes, about 5 to about 20 minutes, or within about 10 minutes. In any embodiment of this process, the solvent may be amyl alcohol, and the antisolvent may be n-heptane, hexane, pentane and octane, and preferably n-heptane or octane.

In any embodiment of this process, the antisolvent may be used in an amount of about 2 to about 30 vol, about 5 to about 20 vol, or about 10 vol. Preferably, the alkane is cooled to a temperature of about 0°C to about 10°C, about 0 to about 5°C, or about 0°C to about 4°C, or about 2°C, optionally with stirring.

[0061] In embodiments, the mixture obtained in step c) is further kept for about 1 to about 10 days, about 2 to about 9 days, or about 2 to about 7 days. The mixture may optionally be stirred at this time. The mixture may be at a temperature of about -20°C to about 10°C, about -20°C to about 5°C, or about -20 to about 2°C.

[0062] Step (d) may comprise isolation of Oteseconazole Form 01 by centrifuge, decantation, or by filtering the suspension, optionally with washing. Step (e) may comprise drying by nitrogen or air or under vacuum. Drying may be performed at a temperature of about 40 to about 60°C, in embodiments about 40 to about 50°C, and in yet other embodiments about 45°C, when the drying is under vacuum (in embodiments at a reduced pressure of: about 1 to about 200 mbar, in embodiments about 1 to about 100 mbar, about 1 to about 50 mbar, about 5 to about 40 mbar or about 20 mbar). [0063] The present disclosure also relates to a crystalline form of Oteseconazole which is obtainable by any of the above described processes and embodiments thereof.

[0064] The present disclosure further encompasses crystalline Oteseconazole: Piperazine. Crystalline Oteseconazole: Piperazine may be a co-crystal of Oteseconazole and Piperazine. [0065] The present disclosure includes a crystalline Oteseconazole: Piperazine, designated Form PCC1. The crystalline Form PCC1 of Oteseconazole: Piperazine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 9.2, 12.2, 18.5, 22.5 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. [0066] Crystalline Form PCC1 of Oteseconazole: Piperazine may be further characterized by an X-ray powder diffraction pattern having peaks at 9.2, 12.2, 18.5, 22.5 and 23.5 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 6.1, 10.5, 13.5, 15.6 and 27.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0067] Alternatively, crystalline Oteseconazole: Piperazine may be characterized by an XRPD pattern having peaks at 6.1, 9.2, 10.5, 12.2, 13.5, 15.6, 18.5, 22.5, 23.5 and 27.9 degrees 2-theta ± 0.2 degrees 2-theta.In one embodiment of the present disclosure, crystalline Form PCC1 of Oteseconazole: Piperazine is isolated.

[0068] Crystalline Form PCC1 of Oteseconazole: Piperazine may be an anhydrous form. In embodiments, crystalline Oteseconazole: Piperazine Form PCC1 contains 0.5% (w/w) or less of water or organic solvents.

[0069] In another embodiment of the present disclosure, crystalline Oteseconazole: Piperazine Form PCC1 is polymorphically pure.

[0070] In preferred embodiment, crystalline Oteseconazole: Piperazine Form PCC1 contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Oteseconazole: Piperazine as measured, for example, by XRPD.

[0071] Crystalline Form PCC1 of Oteseconazole: Piperazine may be characterized by each of the above characteristics alone or by all possible combinations, e.g., an XRPD pattern having peaks at 9.2, 12.2, 18.5, 22.5 and 23.5 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof. [0072] The present disclosure relates to crystalline Oteseconazole: Piperazine and a solid state form thereof. The present disclosure also relates to pharmaceutical compositions including the solid state form of Oteseconazole: Piperazine.

[0073] In some embodiments the disclosure relates to processes for the preparation of crystalline Oteseconazole: Piperazine. In any embodiment, the process comprises crystallising Oteseconazole : Piperazine from a mixture in a solvent. In a preferred embodiment, the solution is prepared by combining a solution of Oteseconazole in a solvent with piperazine to form a mixture, and precipitating Oteseconazole : Piperazine from the mixture. In one embodiment the a process may comprise: a) dissolving Oteseconazole in solvent; b) optionally filtering; c) combining the solution with piperazine; d) precipitating crystalline Oteseconazole : piperazine; e) optionally isolating crystalline Oteseconazole : piperazine; and f) optionally drying the Oteseconazole : piperazine.

[0074] In any embodiment of the process, the solvent in step (a) may be any suitable solvent for Oteseconazole. The solvent may be a ketone, an ether, alcohol or a nitrile, more preferably a C3-6 ketone, a C4-6 ether, a C2-6 alcohol, or acetonitrile. More preferably the solvent is selected from acetone, THF, 2-propanol or acetonitrile, and most preferably acetone.

[0075] In any embodiment of the process, the solvent (preferably acetone) in step (a) is used in an amount of about 0.5 to 40 vol, about 1 to 20 vol, about 1 to 10 vol, about 1 to 5 vol, about 1 to about 3, and preferably about 2 vol, in relation to Oteseconazole.

[0076] The mixture in step (a) may be at a temperature of about 15°C to about 35°C , about 20°C to about 30°C, about 22°C to about 27°C, or about 25°C.

[0077] Step (b) may comprise adding piperazine to the solution in step (a). The piperazine may be added in an amount of about 0.5 to about 1.4 molar equivalents, about 0.5 to about 1.2 molar equivalents, about 0.5 to about 0.8 molar equivalents, about 0.5 to about 0.6 molar equivalents, or about 0.5 molar equivalents, relative to Oteseconazole.

[0078] In any embodiment of this process, step (d) may comprise cooling the mixture of step (c), or by solvent evaporation. Preferably step (d) comprises solvent evaporation, more preferably by exposure to room temperature, to form a precipitate of Oteseconazole : piperazine. Preferably the mixture in step (d) is kept open at room temperature for solvent evaporation, preferably for about 24 to about 70 hours, about 24 to about 48 hours or about 24 hours.

[0079] The Oteseconazole : piperazine may be isolated in step (e) by filtration, centrifuge or decantation. Step (f) may comprise drying the resulting crystalline Oteseconazole : piperazine Form OCC1 by any suitable process, for example by nitrogen or air or under vacuum. Any suitable drying time may be used, for example, in embodiments the drying is carried out over a period of about 0.5 to about 40 hours, about 10 to about 30 hours, about 15 to about 20 hours, or about 18 hours. The drying may be conducted at reduced pressure or a vacuum. When the drying is carried out under reduced pressure or a vacuum, a reduced pressure of about 1 or about 200 mbar, about 1 to about 100 mbar, about 1 to 50 mbar, and particularly about 5 to about 40 mbar or more particularly, about 20 mbar, is used. Alternatively, the drying may be carried out under a flow of nitrogen or air or under vacuum. Drying under a flow of nitrogen or air may be performed at a temperature of about 20°C to about 50°C, about 20°C to about 40°C, and in some embodiments about 30°C.

[0080] Oteseconazole : piperazine Form PCC1 can alternatively be prepared by solvent- antisolvent crystallization of a solution comprising Oteseconazole : Piperazine in a solvent. In any embodiment, the above crystalline Oteseconazole : piperazine Form PCC1 can be prepared by a process comprising:

(a) preparing a solution comprising Oteseconazole and piperazine in one or more organic solvents;

(b) combining the solution with an antisolvent to precipitate Oteseconazole :

Piperazine;

(c) optionally isolating Oteseconazole : Piperazine; and

(d) optionally drying the Oteseconazole : Piperazine Form PCC1.

[0081] In any embodiment, the solvent may be an ether or a ketone, more preferably a C4-6 ether or a C3-6 ketone, and particularly THF or acetone. The solution in step (a) may optionally be heated, optionally to a temperature of about 35°C to about 50°C, about 35°C to about 45°C, or about 40°C. The solution in step (a) may be prepared by combining piperazine with a solution of Oteseconazole in the solvent. The solution of Oteseconazole may be heated to a temperature of about 35°C to about 50°C, about 35°C to about 45°C, or about 40°C before combining with piperazine. The solution of Oteseconazole may be filtered to remove insoluble materials prior to combining with piperazine. In step (a) piperazine may be added to a solution of Oteseconazole in the solvent. The addition may be at the heated temperature. The mixture in step (a) may be stirred at a temperature of about 35°C to about 50°C, about 35°C to about 45°C, or about 40°C. The THF or acetone may be present at an amount of about 1 to about 20 vol, in embodiments about 5 to about 10 vol, and in other embodiments, about 3 vol of THF or acetone is used. In embodiments, about 0.5 to 1.0 equivalents of piperazine, preferably about 0.5 to 0.8 equivalents and preferably 0.5 equivalents of piperazine is added to the solution. Preferably, the mixture comprising Oteseconazole and piperazine in THF or acetone is at about 30-50°C, in yet another embodiments 40°C, optionally with stirring, and cooling to 2-10°C, in embodiments to 4°C. The mixture may be cooled prior to step (b). The cooling may be to a temperature of about 0°C to about 25°C, about 2°C to about 25°C or about 2°C to about 10°C, or about 4°C. Step (b) may comprise adding an antisolvent to the mixture in step (a). The addition may be dropwise. The antisolvent may be an alkane, preferably a C5-10 alkane, particularly a C5-8 alkane, and more preferably n-heptane. In any embodiment of this process, the solvent is THF or acetone, and the antisolvent is n-heptane. The antisolvent (preferably n-heptane) may be cooled prior to combining. In embodiments, the antisolvent (preferably heptane) is cooled before addition to the mixture, preferably to a temperature of about -5°C to about 15°C, about 1 to about 10°C, or preferably about 1 to about 5°C, or about 4°C. In embodiments, n-heptane is used in an amount of about 10 to 30 ml per gram of Oteseconazole, about 20 to about 30 ml per gram of Oteseconazole, and particularly about 15 ml per gram of Oteseconazole. In embodiments, the mixture is stirred during the addition of n-heptane. In any embodiment, the process comprises: a) preparing solution of Oteseconazole and piperazine in THF or acetone, preferably by heating to a temperature of about 35°C to about 45°C, or about 40°C, optionally with stirring, cooling and combining with n-heptane, preferably cooled heptane; b) optionally isolating crystalline Oteseconazole: piperazine Form PCC1, optionally by filtration; and c) optionally drying.

[0082] In embodiments, in step (a) n-heptane is added to the mixture comprising Oteseconazole and piperazine in THF or acetone. The n-heptane may be added dropwise.

[0083] In embodiments, the ratio of THF or acetone to n-heptane is about 1 :0.5 to about 1:10, about 1 : 1 to about 1 : 8, about 1 :3 to about 1 :7, or about 1 :4 to about 1 :6, or about 1:5. [0084] Following the addition of n-heptane to Oteseconazole and piperazine solution, the mixture may be maintained, preferably with stirring, for a suitable period of time until precipitation obtained, in embodiments for about 1-10 hours, or about 2 hours. The mixture is preferably maintained at 2-10°C, in embodiments at 4°C.

[0085] In any embodiment of the above process, step (b) may include isolation of crystalline Oteseconazole: piperazine Form PCC1. The isolation may be done by filtering the suspension formed in step (a), optionally under nitrogen environment. Alternatively, the isolation can be carried out by decantation or by centrifuge. Following the isolation, the product may be washed, and optionally dried.

[0086] In any embodiment of the above described processes, the product may be dried after isolating. In embodiments, the drying is carried out in a vacuum oven. The drying step (c) may be carried out at any suitable temperature, for example, at about 20 to about 50°C, about 25 to about 40°C or about 30°C in a vacuum oven. Any suitable drying time may be used, for example, in embodiments the drying is carried out over a period of about 6 to about 120 hours, about 10 to about 48 hours, about 12 to about 30 hours, or about 24 hours. The drying may be conducted at reduced pressure or a vacuum. When the drying is carried out under reduced pressure or a vacuum, a reduced pressure of about 1 or about 200 mbar, about 1 to about 100 mbar, about 1 to 50 mbar, and particularly about 5 to about 40 mbar or more particularly, about 20 mbar, is used. Alternatively, the drying step (c) may be carried out under a flow of nitrogen or air or under vacuum. Drying under a flow of nitrogen or air may be performed at a temperature of about 20 to about 50°C, about 40 to about 50°C, and in some embodiments about 45°C.

[0087] The present disclosure also relates to a crystalline form of Oteseconazole : Piperazine, which is obtainable by any of the above described processes and embodiments thereof.

[0088] The above crystalline polymorph can be used to prepare other crystalline polymorphs of crystalline Oteseconazole: Piperazine and their solid state forms.

[0089] The present disclosure provides the above described crystalline polymorphs of Oteseconazole and crystalline Oteseconazole: Piperazine for use in the preparation of pharmaceutical compositions comprising Oteseconazole and crystalline Oteseconazole: Piperazine and/or crystalline polymorphs thereof. [0090] The present disclosure also encompasses the use of crystalline polymorphs of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Oteseconazole, crystalline Oteseconazole: Piperazine and/or crystalline polymorphs thereof.

[0091] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure with at least one pharmaceutically acceptable excipient.

[0092] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0093] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0094] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0095] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[0096] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0097] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [0098] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0099] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[00100] In liquid pharmaceutical compositions of the present invention, Oteseconazole and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[00101] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[00102] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[00103] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[00104] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[00105] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00106] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[00107] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00108] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.

[00109] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00110] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[00111] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00112] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00113] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00114] A pharmaceutical formulation of Oteseconazole and crystalline Oteseconazole: piperazine can be administered. Oteseconazole and crystalline Oteseconazole: piperazine may be formulated for administration to a mammal, in embodiments to a human, by injection. Oteseconazole and crystalline Oteseconazole: piperazine can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[00115] The crystalline polymorphs of Oteseconazole, crystalline Oteseconazole: Piperazine and the pharmaceutical compositions and/or formulations of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure can be used as medicaments, in embodiments in the treatment of acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC) , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g., cryptococcal meningitis), or mucormycosis. Optionally, the crystalline polymorphs of Oteseconazole, crystalline Oteseconazole: Piperazine and the pharmaceutical compositions and/or formulations of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure can be used as medicaments for treating candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and more preferably RVVC.

[00116] The present disclosure also provides methods of treating acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC) , or tinea pedis, onychomycosis, candidiasis, meningitis (e.g. cryptococcal meningitis), or mucormycosis; preferably candidiasis, Acute Vulvovaginal Candidiasis or Recurrent Vulvovaginal Candidiasis (RVVC); and more preferably RVVC, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorph of Oteseconazole and crystalline Oteseconazole: Piperazine of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.

[00117] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way. [00118] Further aspects and embodiments of the present disclosure are set out in the following numbered clauses: A crystalline form of Oteseconazole, designated Form 01, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 11.0, 12.8, 17.3, 17.7 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations thereof. Crystalline Oteseconazole according to Clause 1, which is further characterized by an X- ray powder diffraction pattern having any one, two, three, four or five additional peaks selected from 14.9, 18.9, 21.5, 23.2 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Oteseconazole according to Clause 1 or Clause 2, which is characterized by an XRPD pattern having peaks at 11.0, 12.8, 14.9, 17.3, 17.7, 18.9, 21.5, 23.2, 24.5 and 26.7 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Oteseconazole, designated Form 01, which is characterized by an XRPD pattern having peaks at 11.0, 12.8, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2- theta; and one, two, or three additional peaks at 16.6, 23.2, and 28.0 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Oteseconazole according to Clause 4, which is characterized by an XRPD pattern having peaks at 11.0, 12.8, 16.6, 17.3, 23.2, 26.7, and 28.0 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Oteseconazole according to any of Clauses 1, 2, 3, 4 or 5, which is further characterized by:

- an absence of a peak at 19.9 degrees 2-theta ± 0.2 degrees 2-theta; or

- an absence of a peak at 20.8 degrees 2-theta ± 0.2 degrees 2-theta; or

- an absence of peaks at 19.9 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Oteseconazole, designated Form 01, which is characterized by an XRPD pattern having peaks at 11.0, 12.8, 17.3, and 26.7 degrees 2-theta ± 0.2 degrees 2- theta; and

- an absence of a peak at 19.9 degrees 2-theta ± 0.2 degrees 2-theta; or

- an absence of a peak at 20.8 degrees 2-theta ± 0.2 degrees 2-theta; or

- an absence of peaks at 19.9 and 20.8 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Oteseconazole according to Clause 7, which is further characterized by an XRPD having one, two, or three additional peaks at 16.6, 23.2, and 28.0 degrees 2- theta ± 0.2 degrees 2-theta. Crystalline Oteseconazole according to any of Clauses 1, 2, 3, 4, 5, 6, 7, or 8, which is an anhydrous form, preferably wherein the crystalline form contains 0.5% (w/w) or less of water or organic solvents. Crystalline Oteseconazole according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, or 9, which is isolated. Crystalline Oteseconazole according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is polymorphically pure. Crystalline Oteseconazole according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, which is substantially free of any other solid state forms of Oteseconazole. Crystalline Oteseconazole according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% (w/w) of any other forms of Oteseconazole. Oteseconazole: Piperazine. Oteseconazole :Piperazine according to Clause 14, which is crystalline. Crystalline Oteseconazole: Piperazine according to Clause 15, which is a co-crystal of Oteseconazole and Piperazine. Crystalline Oteseconazole: Piperazine according to any of Clauses 14, 15 or 16, wherein the molar ratio of Oteseconazole and Piperazine is 1: 1.5 to 1.5: 0.5, 1: 1.25 to 1.25: 0.5, or about 1:0.5. Crystalline Oteseconazole : Piperazine according to any of Clauses 14, 15, 16, or 17, designated Form PCC1, which is characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X- ray powder diffraction pattern having peaks at 9.2, 12.2, 18.5, 22.5 and 23.5 degrees 2- theta ± 0.2 degrees 2-theta; and combinations thereof. Crystalline Oteseconazole: Piperazine according to Clause 18, which is further characterized by an X-ray powder diffraction pattern having any one, two, three, four or five additional peaks selected from 6.1, 10.5, 13.5, 15.6 and 27.9 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Oteseconazole: Piperazine according to any of Clauses 14, 15, 16, 17, 18, or

19, which is characterized by an XRPD pattern having peaks at 6.1, 9.2, 10.5, 12.2, 13.5, 15.6, 18.5, 22.5, 23.5 and 27.9 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Oteseconazole: Piperazine according to any of Clauses 14, 15, 16, 17, 18, 19, or 20, which is isolated. Crystalline Oteseconazole: Piperazine according to any of Clauses 14, 15, 16, 17, 18, 19,

20, or 21, which is an anhydrous form, preferably wherein the crystalline form contains 0.5% (w/w) or less of water or organic solvents. Crystalline Oteseconazole: Piperazine according to any of Clauses 14, 15, 16, 17, 18, 19, 20, 21, or 22, which is polymorphically pure. Crystalline Oteseconazole : Piperazine according to any of Clauses 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, which contains no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Oteseconazole: Piperazine. Use of a product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, for preparing other crystalline forms of Oteseconazole, salts of Oteseconazole or crystalline forms thereof, or solvates of Oteseconazole or crystalline forms thereof. Use of a product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, for preparing pharmaceutical compositions of Oteseconazole or Oteseconazole : Piperazine. A pharmaceutical composition comprising a product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, and at least one pharmaceutically acceptable excipient. Use of a product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, for the preparation of a pharmaceutical composition and/or formulation, preferably wherein the pharmaceutical formulation is for oral administration, and more preferably wherein the pharmaceutical composition is a solid dosage form, particularly a tablet or a capsule. 29. A process for preparing the pharmaceutical composition according to Clause 27, comprising combining a product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, with at least one pharmaceutically acceptable excipient.

30. A product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, or a pharmaceutical composition according to Clause 27, for use as a medicament.

31. A product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, or a pharmaceutical composition according to Clause 27, for use according to Clause 30, in the treatment of Acute Vulvovaginal Candidiasis, Recurrent Vulvovaginal Candidiasis (RVVC), tinea pedis, onychomycosis, candidiasis, meningitis, cryptococcal meningitis, or mucormycosis; preferably candidiasis, Acute Vulvovaginal Candidiasis, Recurrent Vulvovaginal Candidiasis (RVVC); and more preferably Recurrent Vulvovaginal Candidiasis.

32. A method of treating Acute Vulvovaginal Candidiasis, Recurrent Vulvovaginal Candidiasis (RVVC), tinea pedis, onychomycosis, candidiasis, meningitis, cryptococcal meningitis, or mucormycosis; preferably candidiasis, Acute Vulvovaginal Candidiasis, Recurrent Vulvovaginal Candidiasis (RVVC); and more preferably Recurrent Vulvovaginal Candidiasis, comprising administering a therapeutically effective amount of a crystalline product according to any of Clauses 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, or a pharmaceutical composition according to Clause 27, to a subject in need of the treatment.

Powder X-ray Diffraction ("XRPD") method

[00119] XRPD analysis was performed on ARL (SCINTAG) powder X-Ray diffractometer model X’TRA equipped with a solid state detector. Copper radiation of 1.5418 A was used.

Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size:

0.05°, and a rate of 3 deg/min. EXAMPLES

Preparation of starting materials

[00120] Oteseconazole can be prepared according to methods known from the literature, for example U.S. Patent No. 8,236,962.

Example 1. Preparation of Oteseconazole Form Ol

[00121] Oteseconazole (0.04 grams, 0.076 mmol) was mechanically stirred in No-butanol (0.08 ml, 2V) at room temperature to give a clear solution. The obtained clear solution was stirred at room temperature for about 24 hours to give a precipitation. The precipitant was isolated by centrifuge to afford a solid, which was characterized by X-ray powder diffraction as Oteseconazole form Ol (Figure 1).

Example 2. Preparation of Oteseconazole Form Ol

[00122] Amyl-alcohol (0.09 ml, 3 V) was added to Oteseconazole (0.03 grams, 0.057 mmol) at room temperature to give a slurry. The obtained slurry was magnetically stirred and heated upon 40°C over a period of about 30 minutes to give a clear solution. The obtained hot clear solution was mechanically filtrated upon a filter disk. The obtained clear hot filtrate was then added drop- wise to a cold stirred alkane solvent such as n-heptane, hexane, pentane and octane (0.9 ml, 10V), kept at about 2°C (±2°C), to give a precipitant followed by stirring at about 2°C (±2°C) during about 48 hours. The precipitation was then isolated by centrifuge to afford a solid, which was characterized by X-ray powder diffraction as Oteseconazole Form Ol.

Example 3. Preparation of crystalline Oteseconazole: Piperazine Form PCC1.

[00123] Oteseconazole (800 mg, 1.52 mmol) was dissolved in acetone (2V, 1.6 ml) at room temperature. The obtained solution was mechanically filtrated using filter disk at room temperature. Next, piperazine (65.3 mg, 0.76 mmol, 0.5 eq.) was added to the clear solution at room temperature. The clear mixture was allowed to slowly volatilize at room temperature to precipitate a solid. The obtained solid was then dried in a vacuum oven at 30°C over a period of about 18 hours and analyzed by XRPD to confirm crystalline Oteseconazole: Piperazine Form PCC1.

Example 4. Preparation of Oteseconazole Form Ol

[00124] Oteseconazole (0.03 grams, 0.057 mmol) was added to iso-butanol (0.12 ml, 4V) at 50°C, under stirring to give clear solution. Then, alkane anti-solvent such as n-heptane (0.9 ml, 30V) or octane (0.45ml, 15V) was added drop-wise to the clear solution at 50°C, under stirring. The reaction mixture was cooled spontaneously to room temperature to afford precipitant. The precipitation was then isolated by centrifuge to obtain Oteseconazole form 01.

Example 5. Preparation of Oteseconazole Form Ol

[00125] Oteseconazole (0.03 grams, 0.057 mmol) was added to ethyl-formate (0.09 ml, 3 V) at 40°C, under stirring to give clear solution. Then, one of the alkane anti-solvent such as n-heptane, octane, cyclohexane or petroleum-ether (0.45 ml, 15 V) was added drop-wise to the clear solution at 40°C, with stirring. The reaction mixture was cooled spontaneously to room temperature followed by cooling to -20°C. The reaction mixture was kept at -20°C for about 7 days to afford precipitant. The precipitation was then isolated by centrifuge to obtain Oteseconazole form Ol.

Example 6. Preparation of Oteseconazole Form Ol

[00126] Oteseconazole (0.03 grams, 0.057 mmol) was added to cyclohexanol (0.3 ml, 10V) at 40°C, under stirring to give clear solution. Then, n-heptane or petroleum ether (0.45 ml, 15 V) was added drop-wise to the clear solution at 40°C, with stirring. The reaction mixture was cooled spontaneously to room temperature followed by cooling to -20°C. The reaction mixture was kept at -20°C for about 7 days to afford precipitant. The precipitation was then isolated by decantation to obtain Oteseconazole form Ol.

Example 7. Preparation of crystalline Oteseconazole:piperazine Form PCC1 [00127] Oteseconazole (1 gram, 1.89 mmol) was added to THF (3 ml, 3 V) at 40°C, under stirring to give clear solution. The obtained hot clear solution was mechanically filtrated upon filter disk. Then, piperazine (0.5 eq., 0.945 mmol) was added to the stirred solution upon 40°C. The reaction mixture was stirred at 40°C for additional 10 minutes followed by cooling spontaneously to room temperature. Next, the clear mixture was cooled to 4°C and continues stirring upon this temperature, followed by addition of cold n-heptane (15ml, 15 V) and kept with stirring for minimum 2 hours at 4°C to give precipitant. The precipitation was then isolated by vacuum filtration. The isolated solid was dried in vacuum oven at 30°C for over-night to afford dry solid, which was characterized by X-ray powder diffraction as crystalline Oteseconazole: piperazine Form PCC1. Same procedure can be used but using acetone instead of THF.