Amorphous (A-polymorphic) Sirobin

Abstract

Compositions comprising amorphous silybin are disclosed herein. The amorphous silybin can be synthetic a-polymorphic silybin. Also disclosed herein are methods of treatment using amorphous silybin and methods of manufacturing amorphous silybin.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 350,828, filed on June 9, 2022, which is hereby incorporated by reference in its entirety.

[0002] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the incorporated publications and patents or patent applications conflict with the disclosure contained herein, this specification shall supersede and / or prevail over any such conflicting material.

Background Art

[0003] Silibinin has been studied for use in several therapeutic indications. Compositions containing silibinin, such as amorphous (e.g., a-polymorphic) silibinin, are useful for the treatment of such therapeutic indications. Although there is ongoing debate among researchers as to where the therapeutic window of silibinin lies, it is generally understood that there is a narrow therapeutic window where therapeutic effects are not expected and undesirable effects are expected.

Summary of the Invention

[0004] In one particular exemplary case, silibinin is used therapeutically in crystalline form. In some instances, the crystalline form of a therapeutic agent can cause difficulties in achieving a consistent targeted therapeutic effect, pharmacokinetics, release rate, etc. For example, in some cases, a change in the form of a therapeutic agent can increase or decrease the release and / or bioavailability of the therapeutic agent. Such a change in release rate can be problematic when targeting a narrow therapeutic window. Thus, there is a need for amorphous (e.g., a-polymorphic) silibinin synthesized without generating the crystalline form of silibinin. Typically, the amorphous silibinin concentration is expected to exhibit reduced physical stability and silibinin has a tendency to crystallize over time. Thus, there is a further need to provide a stable amorphous silibinin that provides increased bioavailability of the amorphous composition while avoiding typical stability and crystallization tendencies associated with amorphous compositions.

[0005] In certain embodiments of the present specification, provided is silybin substantially free of amorphous (e.g., a-polymorphic) silybin or crystalline silybin (e.g., less than 10 wt%, less than 5 wt%, less than 2 wt%, less than 1 wt%, or less than 1 wt% crystalline silybin relative to total silybin). In some embodiments of the present specification, provided is a composition (e.g., comprising a plurality of discrete particles) comprising (i) a carrier component and (ii) a silybin component comprising amorphous (e.g., a-polymorphic) silybin. In some embodiments, the carrier component is optional. In some embodiments, the composition comprises a plurality of discrete particles, and each of the plurality of discrete particles independently comprises at least a portion of the carrier component and at least a portion of the silybin component (e.g., as determined by X-ray powder diffraction (XRPD), melting point, differential scanning calorimetry (DSC), solid state nuclear magnetic resonance (SSNMR), or polarized light microscopy). In some embodiments, at least 50 wt% (e.g., 60 wt% or more, 70 wt% or more, 80 wt% or more, or 90 wt% or more) of the silybin component is amorphous (e.g., a-polymorphic) (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized light microscopy). In some embodiments, one or more of the plurality of discrete particles has a ratio of carrier component to silybin component of about 1:99 to about 99:1 (e.g., about 1:99 to about 99:10, about 25:75 to about 75:25, about 40:60 to about 60:40, or about 40:60 to about 90:10, or about 80:20 to about 50:50) (e.g., on average). In some embodiments, each of the plurality of discrete particles has a ratio of carrier component to silybin component of about 1:99 to about 99:1 (e.g., about 1:99 to about 99:10, about 25:75 to about 75:25, about 40:60 to about 60:40, or about 40:60 to about 90:10, or about 80:20 to about 50:50) (e.g., on average). In some embodiments, the composition has a ratio of carrier component to silybin component of about 1:99 to about 99:1 (e.g., about 1:99 to about 99:10, about 25:75 to about 75:25, about 40:60 to about 60:40, or about 40:60 to about 90:10, or about 80:20 to 50:50) (e.g., on average).In some embodiments, at least one discrete particle of the plurality of discrete particles includes at least one discrete domain embedded in a matrix. In some embodiments, at least one discrete particle of the plurality of discrete particles includes a solid or semi-solid dispersion of silibinin in a carrier component. In some embodiments, at least one discrete particle of the plurality of discrete particles includes a solid solution or semi-solid solution of silibinin in a carrier component. In some embodiments, the matrix includes a portion of the carrier component and the discrete domain includes a portion of the silibinin component. In some embodiments, the matrix includes a portion of the silibinin component and the discrete domain includes a portion of the carrier component. In some embodiments, the composition further comprises an additional agent selected from the group consisting of a stimulant, an antihistamine, an antiemetic, an antidepressant, an anti-inflammatory agent, a growth factor, a lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, or a 5HT receptor antagonist, and combinations thereof. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the composition is selected from the group consisting of a spray-dried composition, a freeze-dried composition, a drum-dried composition, a hot-melt extrusion composition, a precipitation composition (e.g., crash precipitation), a supercritical fluidized composition, and a pulse combustion dried composition. In some embodiments, the composition is selected from the group consisting of a spray-dried composition, a wet granulation / fluid bed dried composition, a wet granulation / microwave dried composition, a wet granulation / tray dried composition, a freeze-dried composition, a drum-dried composition, a hot-melt extrusion composition, a precipitation composition (e.g., crash precipitate), a supercritical fluidized composition, and a pulse combustion dried composition. In some embodiments, the composition is a spray-dried composition or a hot-melt extrusion composition.In some embodiments, at least a portion of the carrier constituent is selected from the group consisting of acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co-vinyl acetate, polyacrylic acid (PAA), polyvinyl alcohol, hydroxypropylmethylcellulose acetate succinate (HPMCAS), poly(ethylene glycol-propylene glycol-ethylene glycol) triblock copolymer, cholesterol, cholesterol ester, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose (e.g., cellulose conjugate), sodium stearoyl lactate sugar, carrageenan, monoglyceride, diglyceride, polyethylene glycol (PEG), hydroxypropylmethylcellulose (HPMC), and pregelatinized starch. In some embodiments, the silybin constituent is substantially free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized light microscopy). In some embodiments, the silybin constituent is completely free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized light microscopy).

[0006] The present disclosure also provides a plurality of discrete particles comprising (i) a carrier component comprising at least one carrier, and (ii) a silybin component comprising amorphous (e.g., a-polymorphic) silybin (as determined by XRPD, DSC, melting point, SSNMR, or polarized microscopy). In some embodiments, at least one discrete particle comprises at least one discrete domain embedded in a matrix, the matrix comprising a portion of the carrier component and the discrete domain comprising a portion of the silybin component. In some embodiments, at least one discrete particle comprises at least one discrete domain embedded in a matrix, the matrix comprising a portion of the silybin component and the discrete domain comprising a portion of the carrier component. In some embodiments, each of the plurality of discrete particles comprises (i) at least a portion of the carrier component and (ii) at least a portion of the silybin component. In some embodiments, the plurality of discrete particles are selected from the group consisting of spray-dried particles, freeze-dried particles, drum-dried particles, hot melt extrusion particles, precipitated particles (e.g., crash precipitation), supercritical fluidized particles, and pulse combustion dried particles. In some embodiments, the plurality of discrete particles are selected from the group consisting of spray-dried particles, wet granulation / fluid bed dried particles, wet granulation / microwave dried particles, wet granulation / tray dried particles, freeze-dried particles, drum-dried particles, hot melt extrusion particles, precipitated particles (e.g., crash precipitation), supercritical fluidized particles, and pulse combustion dried particles. In some embodiments, one or more of the plurality of discrete particles have a ratio of carrier component to silybin component of about 1:99 to about 99:1 (e.g., about 1:99 to about 99:10, about 25:75 to about 75:25, or about 40:60 to about 60:40, or about 40:60 to about 90:10, or about 80:20 to 50:50) (e.g., on average). In some embodiments, each particle of the plurality of discrete particles has a ratio of carrier component to silybin component of about 1:99 to about 99:1 (e.g., about 1:99 to about 99:10, about 25:75 to about 75:25, or about 40:60 to about 60:40, or about 40:60 to about 90:10, or about 80:20 to 50:50) (e.g., on average).In some embodiments, at least one discrete particle of the plurality of discrete particles comprises a solid or semi-solid dispersion of silybin in a carrier component. In some embodiments, at least one discrete particle of the plurality of discrete particles comprises a solid solution or semi-solid solution of silybin in a carrier component. In some embodiments, at least a portion of the carrier component is selected from the group consisting of acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co-vinyl acetate, polyacrylic acid (PAA), polyvinyl alcohol, hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(ethylene glycol-propylene glycol-ethylene glycol) triblock copolymer, cholesterol, cholesterol ester, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose (e.g., cellulose conjugate), sodium stearoyl lactate sugar, carrageenan, monoglyceride, diglyceride, polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), and pregelatinized starch. In some embodiments, the plurality of discrete particles further comprises an additional agent selected from the group consisting of a stimulant, an antihistamine, an antiemetic, an antidepressant, an anti-inflammatory agent, a growth factor, a lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, or a 5HT receptor antagonist, and combinations thereof. In some embodiments, at least 50 wt% or more (e.g., 60 wt% or more, 70 wt% or more, 80 wt% or more, or 90 wt% or more) of the silybin component is amorphous (e.g., a-polymorphic) silybin (e.g., determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy).In some embodiments, up to a portion of the silybin has a crystallinity of up to 10% (e.g., 10% or less, 8% or less, 6% or less, 5% or less, or 4% or less, 2% or less, or 1% or less) (e.g., as determined by XRPD, DSC, melting point, SSNMR, or polarized microscopy). In some embodiments, the silybin component is substantially free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy). In some embodiments, the silybin component is completely free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy).

[0007] The present disclosure also provides methods for treating in an individual (e.g., in need of treatment of a mental, behavioral, or neuropsychiatric condition, and / or symptoms thereof), the methods comprising administering to the individual (e.g., in need thereof) any of the compositions disclosed herein (e.g., a plurality of discrete particles). In some embodiments, the mental, behavioral, or neuropsychiatric condition is an attentional or cognitive (e.g., neurocognitive) condition. In some embodiments, the mental, behavioral, or neuropsychiatric condition (e.g., a disorder or condition in a category of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or a non-DSM-5 category) is induced by stress and / or anxiety. In some embodiments, the mental, behavioral, or neuropsychiatric condition (e.g., a disorder or condition in a DSM-5 category or a non-DSM-5 category) is selected from the group consisting of intoxication, anxiety (e.g., post-traumatic stress disorder (PTSD), constructive impulsivity, phobia, or fear), apathy, and depression (e.g., major depressive disorder). In some embodiments, the symptoms of the mental, behavioral, or neuropsychiatric condition are physical, behavioral, emotional, mental, or combinations thereof. In some embodiments, the attentional condition is attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD). In some embodiments, the cognitive condition is mild cognitive impairment, dementia, or Alzheimer's disease.

[0008] The present disclosure also provides a method for producing amorphous (e.g., a-polymorphic) silybin, the method comprising: (i) providing (e.g., synthesizing) silybin components; and (ii) combining the silybin components with carrier components, wherein the carrier components include at least one carrier to produce a silybin-carrier composition; and (iii) treating the silybin-carrier composition to produce one or more particles (e.g., an amorphous composition) comprising amorphous (e.g., a-polymorphic) silybin (e.g., components) and carrier components. In some embodiments, treating comprises selecting from the group consisting of spray drying, wet granulation / fluid bed drying, wet granulation / microwave dyeing, wet granulation / tray drying, freeze drying, drum drying, precipitation (e.g., crash precipitation), hot melt extrusion, supercritical fluidization, and pulse combustion drying. In some embodiments, treating is spray drying. In some embodiments, treating is hot melt extrusion.

[0009] The present disclosure also provides a method for producing an amorphous composition comprising silibinin, the method comprising: (i) synthesizing silibinin constituent components; and (ii) producing an amorphous composition comprising the silibinin constituent components. In some embodiments, the processing is selected from the group consisting of spray drying, freeze drying, drum drying, precipitation (e.g., crash precipitation), hot melt extrusion, supercritical fluidization, and pulse combustion drying. In some embodiments, the processing is spray drying. In some embodiments, the processing is hot melt extrusion. In some embodiments, the amorphous (e.g., a-polymorphic) silibinin is substantially free of crystalline silibinin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy). In some embodiments, the silibinin constituent components are completely free of crystalline silibinin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy). In some embodiments, the synthesis step produces an amorphous (e.g., a-polymorphic) silibinin constituent component that is completely free of crystalline silibinin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy) (e.g., the XRPD scan contains no reflections or peaks). In some embodiments, the synthesizing does not include a crystallization step (e.g., of silibinin). In some embodiments, the synthesis step results in a silibinin constituent component having a chemical purity of at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or 99.5%, and all values therebetween) as determined, for example, by high performance liquid chromatography (HPLC), and containing no more than 2% of a single impurity (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.15%). In some embodiments, at least 50 wt% (e.g., 60 wt% or more, 70 wt% or more, 80 wt% or more, or 90 wt% or more) of the silibinin constituent components is amorphous (e.g., a-polymorphic) silibinin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy). In some embodiments, at least one of one or more particles comprises a solid or semi-solid dispersion of silibinin in a carrier constituent component.In some embodiments, at least one of the one or more particles comprises a solid or semi-solid solution of silibinin in a carrier component. In some embodiments, the silibinin component comprises amorphous (e.g., a-polymorphic) silibinin. In some embodiments, at least a portion of the carrier component is selected from the group consisting of acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co-vinyl acetate, polyacrylic acid (PAA), polyvinyl alcohol, hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(ethylene glycol-propylene glycol-ethylene glycol) triblock copolymer, cholesterol, cholesterol ester, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose (e.g., cellulose conjugate), sodium stearoyl lactylate sugar, carrageenan, monoglyceride, diglyceride, polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), and pregelatinized starch.

[0010] In some embodiments, a composition (e.g., an amorphous composition) produced by any of the methods described herein is provided herein. In some embodiments, differential scanning calorimetry (DSC) is modulated DSC.

[0011] In some embodiments, a method for producing an amorphous composition comprising silibinin is provided herein, the method comprising: (i) synthesizing a silibinin component; and (ii) producing an amorphous composition comprising the silibinin component.

[0012] In some embodiments, generating comprises spray drying, wet granulation / fluid bed drying, wet granulation / microwave drying, wet granulation / tray drying, freeze drying (e.g., lyophilization), drum drying, precipitation (e.g., crash precipitation), hot melt extrusion, supercritical fluidization, or pulse combustion drying. In some embodiments, generating comprises spray drying. In some embodiments, generating comprises freeze drying. In some embodiments, freeze drying or spray drying is performed in the absence of a carrier (e.g., a polymer). In some embodiments, generating comprises freeze drying or spray drying in the presence of one or more sugars. In some embodiments, the one or more sugars comprise mannitol and / or trehalose. In some embodiments, spray drying comprises spray drying in the presence of silicon dioxide.

[0013] In some embodiments, the silybin component is the sole component of the amorphous composition.

[0014] In some embodiments, the amorphous composition is completely free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized light microscopy). In some embodiments, the silybin component is completely free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized light microscopy). In some embodiments, synthesizing provides an a-polymorphic silybin that is completely free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized light microscopy) (e.g., the XRPD scan contains no reflections or peaks). In some embodiments, synthesizing does not include a crystallization step (e.g., of silybin). In some embodiments, generating provides an a-polymorphic silybin that is completely free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized light microscopy) (e.g., the XRPD scan contains no reflections or peaks).

[0015] In some embodiments, synthesizing provides a silybin constituent having a chemical purity of at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or 99.5%, and all values therebetween), for example, as determined by high performance liquid chromatography (HPLC) or reverse phase HPLC, without containing a single impurity exceeding 2% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.15%). In some embodiments, generating provides a silybin constituent having a chemical purity of at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or 99.5%, and all values therebetween), for example, as determined by high performance liquid chromatography (HPLC) or reverse phase HPLC, without containing a single impurity exceeding 2% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.15%). In some embodiments, at least 25 wt%, 50 wt% (e.g., 60 wt% or more, 70 wt%, 75 wt% or more, 80 wt% or more, or 90 wt% or more) of the amorphous composition is α-polymorphic silybin (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized light microscopy). In some embodiments, the silybin constituent consists of amorphous (e.g., α-polymorphic) silybin.

[0016] In some embodiments, the amorphous composition is not a dispersion (e.g., a solid).

[0017] Provided herein is a composition (e.g., an amorphous composition) produced by any one of the claims provided herein.

[0018] Synthetic a-polymorphic silibinin compositions that do not contain crystalline silibinin at all (determined by, for example, XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized microscopy) are provided herein. In some embodiments, the synthetic a-polymorphic silibinin contains no single impurity exceeding 2% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.15%), and has a chemical purity of at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or 99.5%, and all values in between), as determined by, for example, high performance liquid chromatography (HPLC) or reverse phase HPLC. In some embodiments, the synthetic a-polymorphic silibinin has a chemical purity of at least 98%.

[0019] In some embodiments, the synthetic a-polymorphic silibinin is concentrated. In some embodiments, the concentrated synthetic a-polymorphic silibinin composition is a spray-dried a-polymorphic silibinin composition. In some embodiments, the concentrated synthetic a-polymorphic silibinin composition is a lyophilized a-polymorphic silibinin composition. In some embodiments, the synthetic a-polymorphic silibinin further contains one or more sugars (e.g., mannitol, trehalose). In some embodiments, the synthetic a-polymorphic silibinin further contains silicon dioxide.

[0020] In some embodiments, the a-polymorphic silibinin composition does not contain a carrier (e.g., does not contain a polymer). In some embodiments, the a-polymorphic silibinin composition is not a dispersion (e.g., a solid). In some embodiments, the a-polymorphic silibinin composition contains no carrier (e.g., does not contain a polymer) and does not contain crystalline silibinin at all (determined by, for example, XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized microscopy) after storage at a controlled room temperature for 1 to 2 weeks.

[0021] In some embodiments, methods for making synthetic a-polymorphic silybin compositions are provided herein, the methods comprising: (a) providing silybin; (b) deprotecting protected silybin in a reaction solvent to provide silybin; (c) extracting silybin from the reaction solvent into an aqueous medium and washing the aqueous medium with an organic solvent; (d) concentrating the aqueous medium containing silybin; and (e) collecting amorphous (e.g., a-polymorphic) silybin.

[0022] In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, at least 99.5%) of the composition is composed of amorphous silybin.

[0023] In some embodiments, protected silybin is represented by the following structure.

[0024]

Chemical formula

[0025] In some embodiments, each R is independently hydrogen or a protecting group.

[0026] In some embodiments, both Rs are protecting groups. In some embodiments, the protecting group contains benzene. In some embodiments, both Rs are hydrogen. In some embodiments, the protecting group is methylbenzene.

[0027] In some embodiments, deprotecting comprises hydrogenolysis. In some embodiments, the reaction solvent contains alcohol. In some embodiments, the reaction solvent contains methanol. In some embodiments, the organic solvent contains a halocarbon. In some embodiments, the organic solvent contains dichloromethane. In some embodiments, the aqueous medium has a pH of about 9.

[0028] In some embodiments, concentrating includes spray drying. In some embodiments, concentrating includes freeze drying. In some embodiments, the method does not require distillation of an aqueous medium. In some embodiments, the synthetic a-polymorphic silybin composition is at least 98% pure without requiring crystallization.

[0029] In some embodiments, provided herein is pure synthetic a-polymorphic silybin produced by any one of the methods provided herein.

[0030] In some embodiments, provided herein is a composition in which at least 50% of the composition is composed of amorphous silybin.

[0031] In some embodiments, at least 60% (e.g., at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, at least 99.5%) of the composition is composed of amorphous silybin. In some embodiments, the amorphous silybin is at least 10% amorphous (e.g., at least 20% amorphous, at least 25% amorphous, at least 40% amorphous, at least 50% amorphous, at least 60% amorphous, at least 75% amorphous, at least 80% amorphous, at least 90% amorphous, at least 95% amorphous, at least 96% amorphous, at least 97% amorphous, at least 98% amorphous, at least 99% amorphous) as measured by, for example, power X-ray diffraction (XRPD). In some embodiments, the amorphous silybin is present in the composition with a purity of at least 85% (e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, at least 99.5%). In some embodiments, the composition contains less than 20% (e.g., less than 40%, less than 30%, less than 10%, less than 5%, less than 2.5%, less than 1%) by amount of polymer. In some embodiments, the amorphous silybin is not dispersed throughout the polymer matrix.

[0032] In some embodiments, the composition is stable for at least one week (e.g., at least 30 days, at least 60 days, at least 90 days, at least six months, at least one year) (e.g., under ambient conditions) (e.g., physically and / or chemically).

[0033] In some embodiments, silybin has never been crystalline (e.g., as determined by powder X-ray diffraction (XRPD)).

[0034] The novel features of the invention are set forth in detail in the appended claims. The features and advantages of the invention will be better understood by reference to the following detailed description of illustrative embodiments in which the principles of the invention are utilized, and the accompanying drawings (also the "Figure" and "FIG" in this specification).

Brief Description of the Drawings

[0035]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0036] Specific Definitions As used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or a plurality of cells) known to those skilled in the art and their equivalents. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formula, all combinations and sub-combinations of the ranges, as well as specific embodiments therein, are intended to be included. The term "about" when referring to a number or numerical range means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the recited number or numerical range. The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is not intended to exclude other specific embodiments, for example, embodiments of any composition such as the substances, compositions, methods, or processes described herein, from "consisting of" or "consisting essentially of" the recited features.

[0037] As used herein, the term "free from" means containing less than 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, or 0.5%, or an undetectable amount of a characteristic (e.g., crystallinity) or substance (e.g., impurity). As used herein, the term "substantially" means containing at least 99.99%, 99.9%, 99.8%, 99.7%, or 99.5% of a characteristic (e.g., crystallinity or lack thereof) or substance (e.g., shiroside).

[0038] As used herein, the terms "treating", "treatment", or "treat" include reducing, alleviating, ameliorating, curing, managing, alleviating, or soothing a symptom associated with a disease, disease state, condition, or indication (e.g., provided herein) in either a chronic or acute treatment situation. Further, treatment of a disease or disease state described herein includes disclosure of the use of such a compound or composition for the treatment of such a disease, disease state, disorder, or indication.

[0039] The terms "effective amount", "pharmaceutically effective amount", or "therapeutically effective amount" refer to an amount of an agent that is non-toxic but sufficient to provide the desired biological, therapeutic, and / or prophylactic result. The result can be a reduction and / or amelioration of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition or plurality of discrete particles disclosed herein required to provide a clinically significant reduction in a disease or disorder. The appropriate effective amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0040] "Solubility" generally means the amount of a compound dissolved in a solvent. Suitable solvents include aqueous and non-aqueous solvents.

[0041] "Insufficient solubility" means that the amount of a compound dissolved in a solvent is low. Insufficient solubility is not an absolute term and depends on the amount of the compound required for effective treatment of a disease or condition. A compound has low solubility if its solubility is lower than desired for effective treatment of a disease or condition.

[0042] "Enhanced solubility" means higher solubility than a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof alone. Many body fluids such as blood are water-based (aqueous), and thus enhanced solubility in water can be useful since more water-soluble drugs may have higher bioavailability. The exact solubility of a compound in pure water is not the same as in an aqueous solution such as blood, but the solubility of a composition in pure water is often a good indicator of its solubility in other aqueous solutions.

[0043] "Particle" means a particle or body of any size or shape, including large particles (such as those produced by hot melt extrusion) and small particles (such as those produced by spray drying or wet granulation / fluidization, microwave or tray drying).

[0044] Amorphous silibinin In some embodiments herein, a composition (e.g., a solid (e.g., a semi-solid (e.g., amorphous)) or a liquid) (e.g., comprising a plurality of discrete particles) is provided that comprises amorphous (e.g., a-polymorphic) silibinin (e.g., as determined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) (e.g., modulated DSC), melting point, solid state nuclear magnetic resonance (SSNMR), or polarized light microscopy).

[0045] In some embodiments, a composition (e.g., a solid (e.g., a semi-solid (e.g., amorphous)) or a liquid) comprising a silibinin component is provided herein. In some embodiments, amorphous silibinin is synthesized without producing a crystalline (e.g., silibinin) intermediate (a-polymorphic silibinin). In some embodiments, the silibinin component comprises amorphous (e.g., a-polymorphic) silibinin. In some embodiments, the composition comprises a carrier component. In some embodiments, a composition comprising a carrier component and a silibinin component is provided herein.

[0046] In some embodiments of the present specification, a composition comprising a carrier component and a silybin component is provided. In some embodiments of the present specification, a plurality of discrete particles comprising a carrier component and a silybin component are further provided. In some embodiments, the silybin component comprises amorphous (e.g., a-polymorphic) silybin.

[0047] In some embodiments, any one of the compositions (e.g., silybin compositions) provided herein is a (e.g., synthetic) a-polymorphic silybin composition. In some embodiments, an a-polymorphic silybin composition is provided herein. In some embodiments, the a-polymorphic silybin composition provided herein is a synthetic a-polymorphic silybin composition. In some embodiments, the a-polymorphic silybin composition does not (e.g., completely) contain natural components (e.g., mushroom extract). In some embodiments, the a-polymorphic silybin composition does not (e.g., completely) contain crystalline silybin. In some embodiments, the synthetic a-polymorphic silybin composition does not (e.g., completely) contain crystalline silybin. In some embodiments, a synthetic a-polymorphic silybin composition that does not (e.g., completely) contain crystalline silybin as determined by, for example, XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized microscopy is provided herein. In some embodiments, the a-polymorphic silybin composition does not (e.g., substantially) contain crystalline silybin. In some embodiments, the synthetic a-polymorphic silybin composition does not (e.g., substantially) contain crystalline silybin. In some embodiments, a synthetic a-polymorphic silybin composition that does not (e.g., substantially) contain crystalline silybin as determined by, for example, XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized microscopy is provided herein. In some embodiments, the silybin component is the only component of the amorphous composition.

[0048] In some embodiments of the present specification, a composition generated by any one of the methods provided herein is provided. In some embodiments, a composition generated by any one of the methods provided herein is an amorphous composition. In some embodiments, the composition is an amorphous silybin composition. In some embodiments, the composition is an a-polymorphic silybin composition.

[0049] In some embodiments, the silybin (e.g., a-polymorphic silybin) composition provided herein is concentrated. In some embodiments, the silybin (e.g., a-polymorphic silybin) composition provided herein is a spray-dried silybin (e.g., a-polymorphic silybin) composition. In some embodiments, the silybin (e.g., a-polymorphic silybin) composition provided herein is a lyophilized silybin (e.g., a-polymorphic silybin) composition.

[0050] In some embodiments, a composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) is provided herein, and at least 50% of the composition is composed of amorphous (e.g., a-polymorphic) silybin. In some embodiments, a composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) is provided herein, and at least 50% (at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%) of the composition is composed of amorphous (e.g., a-polymorphic) silybin. In some embodiments, a composition (e.g., (e.g., synthetic) a-polymorph composition or amorphous silybin composition) is provided herein, and up to 99.5% (e.g., up to 99%, up to 98.5%, up to 97%, up to 95%, up to 90%, up to 80%, up to 70%, up to 60%) of the composition contains silybin.

[0051] In some embodiments, the composition comprises a silybin (e.g., amorphous (e.g., a-polymorphic) silybin) constituent. In some embodiments, the distinct particles of the plurality of distinct particles comprise a silybin (e.g., amorphous (e.g., a-polymorphic) silybin) constituent. In some embodiments, the plurality of distinct particles comprise a silybin (e.g., amorphous (e.g., a-polymorphic) silybin) constituent. In some embodiments, the silybin constituent comprises silybin. In some embodiments, the silybin constituent comprises silychristin. In some embodiments, the silybin constituent comprises silybin and silychristin. In some embodiments, the silybin constituent comprises amorphous silychristin.

[0052] In some embodiments, in any one of the compositions provided herein, a-polymorphic silybin has never been crystalline, such as at any point during the production of silybin. In some embodiments, in any one of the compositions provided herein, a-polymorphic silybin has never been substantially crystalline, such as at any point during the production of silybin. In some examples, a-polymorphic silybin can take forms of a plurality of different crystalline states, but the a-polymorphic silybin compositions provided herein have never been in any of those crystalline states.

[0053] In some embodiments, the composition consists essentially of amorphous (e.g., a-polymorphic) silybin. In some embodiments, the composition substantially does not contain crystalline silybin (e.g., less than 10 wt%, less than 8 wt%, less than 6 wt%, less than 4 wt%, less than 2 wt%, or less than 1 wt%) (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized light microscopy).

[0054] In some embodiments, in any of the compositions provided herein, at least 25% by weight (e.g., 50% by weight or more, 60% by weight or more, 70% by weight or more, 75% by weight or more, 80% by weight or more, or 90% by weight or more) of the amorphous (e.g., a-polymorphic) silybin composition is amorphous (e.g., a-polymorphic) silybin. In some embodiments, in any of the compositions provided herein, up to 90% by weight (e.g., up to 80% by weight, up to 75% by weight, up to 50% by weight, up to 30% by weight, up to 25% by weight) of the amorphous (e.g., a-polymorphic) silybin composition is amorphous (e.g., a-polymorphic) silybin. In some embodiments, about 25% to about 90% by weight of the amorphous (e.g., a-polymorphic) silybin composition is amorphous (e.g., a-polymorphic) silybin.

[0055] In some embodiments, the plurality of discrete particles consists essentially of amorphous (e.g., a-polymorphic) silybin. In some embodiments, the plurality of discrete particles is substantially free of crystalline silybin (e.g., less than 10% by weight, less than 8% by weight, less than 6% by weight, less than 4% by weight, less than 2% by weight, or less than 1% by weight) (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized light microscopy).

[0056] In some embodiments, the silybin component is substantially free of crystalline silybin (e.g., less than 10% by weight, less than 8% by weight, less than 6% by weight, less than 4% by weight, less than 2% by weight, or less than 1% by weight) (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized light microscopy). In some embodiments, the amorphous (e.g., a-polymorphic) silybin is substantially free of crystalline silybin (e.g., less than 10% by weight, less than 8% by weight, less than 6% by weight, less than 4% by weight, less than 2% by weight, or less than 1% by weight) (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized light microscopy).

[0057] In some examples, the composition comprises an amount of crystalline silybin that is at most 10 wt% (e.g., 10 wt% or less, 8 wt% or less, 6 wt% or less, 4 wt% or less, 2 wt% or less, or 1 wt% or less), as determined by, for example, XRPD, melting point, DSC, SSNMR, or polarized light microscopy. In some examples, the silybin constituent comprises an amount of crystalline silybin that is at most 10 wt% (e.g., 10 wt% or less, 8 wt% or less, 6 wt% or less, 4 wt% or less, 2 wt% or less, or 1 wt% or less), as determined by, for example, XRPD, melting point, DSC, SSNMR, or polarized light microscopy. In some embodiments, the composition is free of crystalline silybin, as determined by, for example, XRPD, melting point, DSC, SSNMR, or polarized light microscopy. In some embodiments, the silybin constituent is free of crystalline silybin, as determined by, for example, XRPD, melting point, DSC, SSNMR, or polarized light microscopy.

[0058] In some examples, the plurality of discrete particles comprises an amount of crystalline silybin that is at most 10 wt% (e.g., 10 wt% or less, 8 wt% or less, 6 wt% or less, 4 wt% or less, 2 wt% or less, or 1 wt% or less), as determined by, for example, XRPD, melting point, DSC, SSNMR, or polarized light microscopy. In some embodiments, the plurality of discrete particles is free of crystalline silybin, as determined by, for example, XRPD, melting point, DSC, SSNMR, or polarized light microscopy.

[0059] In some examples, amorphous (e.g., a-polymorphic) silybin (e.g., a silybin component) contains an amount of crystalline silybin that is at most 10 wt% (e.g., 10 wt% or less, 8 wt% or less, 6 wt% or less, 4 wt% or less, 2 wt% or less, or 1 wt% or less) (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy). In some embodiments, amorphous (e.g., a-polymorphic) silybin (e.g., a silybin component) does not contain any crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy). In some embodiments, not containing any means undetectable (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy). In some examples, an amorphous (e.g., a-polymorphic) silybin composition is an a-polymorphic silybin composition that does not contain any crystalline silybin.

[0060] In some embodiments, in any of the compositions provided herein, amorphous (e.g., a-polymorphic) silybin is at least 10% amorphous (e.g., at least 20% amorphous, at least 25% amorphous, at least 40% amorphous, at least 50% amorphous, at least 60% amorphous, at least 75% amorphous, at least 80% amorphous, at least 90% amorphous, at least 95% amorphous, at least 96% amorphous, at least 97% amorphous, at least 98% amorphous, at least 99% amorphous) (e.g., as measured by XRPD). In some embodiments, in any of the compositions provided herein, amorphous (e.g., a-polymorphic) silybin is at least 60% amorphous. In some embodiments, in any of the compositions provided herein, amorphous (e.g., a-polymorphic) silybin is at most 99.5% amorphous (e.g., at most 95% amorphous, at most 90% amorphous, at most 80% amorphous, at most 70% amorphous, at most 60% amorphous, at most 50% amorphous) (e.g., as measured by XRPD). In some embodiments, in any of the compositions provided herein, amorphous (e.g., a-polymorphic) silybin is about 10% to about 99.5% amorphous when measured by, e.g., XRPD.

[0061] In some embodiments, silybin (e.g., silybin constituents such as amorphous or a-polymorphic silybin) has a (e.g., chemical and / or physical) purity of at least 85 wt%, at least 90 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, at least 99 wt%, or at least 99.5 wt% and all values in between (e.g., indicating the amount of impurities (e.g., substances other than silybin) found in the sample). In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a (e.g., chemical and / or physical) purity of at least 95 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a (e.g., chemical and / or physical) purity of at least 97 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a (e.g., chemical and / or physical) purity of at least 98 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a (e.g., chemical and / or physical) purity of up to 99.5 wt%, up to 99 wt%, up to 98 wt%, up to 97 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a (e.g., chemical and / or physical) purity of up to 99 wt%. In some embodiments, the (e.g., chemical and / or physical) purity of a plurality of discrete particles (e.g., one or more particles) is at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, at least 99 wt%, or at least 99.5 wt%, and all values in between. In some examples, chemical purity is determined by titration, spectroscopy (e.g., infrared, UV-VIS), chromatography (e.g., HPLC TLC (thin layer chromatography) or paper chromatography), polarimetry, mass spectrometry, or a combination thereof). In some examples, chemical purity is calculated as an average (e.g., as the average chemical purity of a sample of particles from a plurality of discrete particles). In some embodiments, physical purity is determined by melting point, XRPD, DSC (e.g., modulated DSC), SSNMR, or polarized microscopy.

[0062] In some embodiments, silybin (e.g., silybin constituent (e.g., amorphous or a-polymorphic silybin)) has a chemical purity of at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, at least 99 wt%, or at least 99.5 wt%, and all values therebetween (e.g., indicating the amount of impurities (e.g., substances other than silybin) found in the sample) (e.g., determined by high performance liquid chromatography (HPLC) or reverse phase HPLC). In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a chemical purity of at least 95 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a chemical purity of at least 97 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a chemical purity of at least 98 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a chemical purity of up to 99.5 wt%, up to 99 wt%, up to 98 wt%, up to 97 wt%. In some embodiments, silybin (e.g., synthetic a-polymorphic silybin) has a chemical purity of up to 99 wt%. In some embodiments, the chemical purity of particles of a plurality of discrete particles (e.g., one or more particles) is at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, at least 99 wt%, or at least 99.5 wt%, and all values therebetween (e.g., determined by HPLC). In some examples, the chemical purity is determined by titration, spectroscopy (e.g., infrared, UV-VIS), chromatography (e.g., HPLC TLC (thin layer chromatography) or paper chromatography), polarimetry, mass spectrometry, or combinations thereof). In some examples, the chemical purity is calculated as an average (e.g., as the average chemical purity of a sample of particles from a plurality of discrete particles).

[0063] In any of the compositions provided herein, in some embodiments, the silybin component comprises at most 1 impurity, at most 2 impurities, or at most 3 impurities. In some embodiments, the silybin component comprises at most 1 impurity, at most 2 impurities, at most 3 impurities, at most 4 impurities, at most 5 impurities, at most 6 impurities, at most 7 impurities, at most 8 impurities, at most 9 impurities, at most 10 impurities, at most 11 impurities, or at most 12 impurities. In some embodiments, the silybin component comprises at least 1 impurity, at least 2 impurities, or at least 3 impurities. In some embodiments, the silybin component comprises at least 1 impurity, at least 2 impurities, at least 3 impurities, at least 4 impurities, at least 5 impurities, at least 6 impurities, at least 7 impurities, at least 8 impurities, at least 9 impurities, at least 10 impurities, at least 11 impurities, or at least 12 impurities. In some embodiments, a single impurity (e.g., in silybin) is not present in a proportion exceeding 2% (e.g., less than 2%, less than 1.5%, less than 1%, less than 0.5%, or less than 0.15%). In some embodiments, a single impurity (e.g., in (e.g., a-polymorphic) silybin) is not present in a proportion exceeding 2%. In some embodiments, a single impurity (e.g., in (e.g., a-polymorphic) silybin) is not present in a proportion exceeding 1%.

[0064] In some embodiments, any one of the compositions provided herein does not contain a carrier. In some embodiments, any one of the compositions provided herein does not contain a polymer. In some embodiments, the (e.g., amorphous (e.g., a-polymorphic)) silybin composition provided herein does not contain a carrier. In some embodiments, the (e.g., amorphous (e.g., a-polymorphic)) silybin composition provided herein does not contain a polymer. In some embodiments, the amorphous (e.g., a-polymorphic) composition provided herein does not contain a polymer. In some embodiments, the amorphous (e.g., a-polymorphic) composition provided herein does not contain a carrier.

[0065] In some embodiments, in any one of the compositions provided herein, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) contains less than 20% (e.g., less than 40%, less than 30%, less than 10%, less than 5%, less than 2.5%, less than 1%) of a polymer. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) contains less than 5% of a polymer. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) contains at least 0.1% (e.g., at least 1%, at least 5%, at least 10%, at least 20%) of a polymer. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) contains from about 0.1% to about 30% of a polymer.

[0066] In some embodiments, any one of the compositions provided herein is not a dispersion (e.g., solid). In some embodiments, any one of the compositions does not contain silybin (e.g., a-polymorphic silybin or amorphous silybin) dispersed throughout a solid such as a polymer matrix.

[0067] In some embodiments, the composition comprises a carrier (e.g., a carrier component). In some embodiments, the plurality of discrete particles comprises a carrier (e.g., a carrier component). In some examples, the carrier (e.g., a carrier component) is an excipient. In some examples, the carrier component comprises one carrier. In some embodiments, the carrier component comprises one or more carriers. In some examples, the carrier component comprises two, three, four, or five carriers.

[0068] In some embodiments, the carrier comprises a polymer. In some embodiments, the carrier comprises a polymeric carrier. In some embodiments, the polymer (carrier) comprises acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co-vinyl acetate, polyacrylic acid (PAA), polyvinyl alcohol (PVA), cholesterol, cholesterol ester, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose (e.g., cellulose conjugate or microcrystalline cellulose), sugar, sodium stearoyl lactate, carrageenan, monoglyceride, diglyceride, polyethylene glycol (PEG), poly(ethylene glycol-propylene glycol-ethylene glycol) triblock copolymer, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), porous calcium silicate, magnesium aluminum metasilicate, and pregelatinized starch, a portion thereof, or a combination thereof (e.g., at least a portion thereof).

[0069] In some embodiments, the carrier (e.g., a polymeric (carrier)) is selected from the group consisting of acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co-vinyl acetate, polyacrylic acid (PAA), polyvinyl alcohol (PVA), cholesterol, cholesterol ester, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose (e.g., cellulose conjugate or microcrystalline cellulose), sugar, sodium stearoyl lactate, carrageenan, monoglyceride, diglyceride, polyethylene glycol (PEG), poly(ethylene glycol-propylene glycol-ethylene glycol) triblock copolymer, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), porous calcium silicate, magnesium aluminum metasilicate, and pregelatinized starch, or at least a part thereof, or a combination thereof.

[0070] In some embodiments, any one of the compositions provided herein may contain a sugar such as any suitable sugar. In some embodiments, any one of the compositions provided herein may contain mannitol, trehalose, sucrose, glucose, dextrose, molasses, and lactose. In some embodiments, the composition contains mannitol. In some embodiments, the composition contains trehalose. In some embodiments, the composition contains sucrose. In some embodiments, the composition contains glucose. In some embodiments, the composition contains sucrose. In some embodiments, the composition contains dextrose. In some embodiments, the composition contains sucrose. In some embodiments, the composition contains molasses. In some embodiments, the composition contains sucrose. In some embodiments, the composition contains lactose. In some examples, sirolimus (e.g., a-polymorphic or amorphous sirolimus) is not present in the sugar matrix. In some examples, the sugar serves to enhance the long-term stability of the compositions provided herein. In some examples, the sugar serves to enhance product handling such as fluidity in spray drying of the compositions provided herein. In some examples, the sugar serves to enhance product handling such as reconstruction of lyophilized products in lyophilization of the compositions provided herein.

[0071] In some embodiments, any one of the compositions provided herein may contain silicon dioxide. In some embodiments, silicon dioxide serves to enhance product handling such as fluidity in spray drying of the compositions provided herein.

[0072] In some embodiments, at least a portion of sirolimus (e.g., sirolimus constituent) comprises amorphous (e.g., a-polymorphic) sirolimus (e.g., % by weight or % by volume) as determined by XRPD, DSC (e.g., modulated DSC), SSNMR, polarized microscopy, spectroscopy, melting point, or solution calorimetry.

[0073] In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) comprises from 1 wt% to 100 wt% (e.g., at least 40 wt%, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 99 wt% or more) of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., an amorphous silybin constituent)). In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a weight percentage of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., an amorphous silybin constituent)) that is 40 wt% or more, 50 wt% or more, 60 wt% or more, 70 wt% or more, 80 wt% or more, 90 wt% or more, 99 wt% or more. In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a weight percentage of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., an amorphous silybin constituent)) that is 99 wt% or less, 90 wt% or less, 80 wt% or less, 70 wt% or less, 60 wt% or less, 50 wt% or less, 40 wt% or less. In some embodiments, the composition (e.g., an amorphous silybin composition) has a weight percentage of silybin (e.g., amorphous silybin (e.g., an amorphous silybin constituent)) that is at least 80 wt%, at least 85 wt%, at least 90 wt%, at least 95 wt% or more.

[0074] In some embodiments, the plurality of discrete particles comprise from 1 wt% to 100 wt% (e.g., at least 40 wt%, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 99 wt% or more) of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., amorphous silybin constituent)). In some embodiments, the plurality of discrete particles have a wt% of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., amorphous silybin constituent)) that is 40 wt% or more, 50 wt% or more, 60 wt% or more, 70 wt% or more, 80 wt% or more, 90 wt% or more, 99 wt% or more. In some embodiments, the plurality of discrete particles have a wt% of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., amorphous silybin constituent)) that is 99 wt% or less, 90 wt% or less, 80 wt% or less, 70 wt% or less, 60 wt% or less, 50 wt% or less, 40 wt% or less. In some embodiments, the plurality of discrete particles have a wt% of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., amorphous silybin constituent)) that is at least 80 wt%, at least 85 wt%, at least 90 wt%, at least 95 wt% or more.

[0075] In some embodiments, the silybin component (e.g., as described herein) comprises from 1 wt% to 100 wt% (e.g., at least 40 wt%, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, at least 99 wt% or more) of silybin (e.g., amorphous (e.g., a-polymorphic) silybin (e.g., amorphous silybin component)). In some embodiments, the silybin component (e.g., as described herein) has a weight percentage of silybin (e.g., amorphous (e.g., a-polymorphic) silybin) that is 40 wt% or more, 50 wt% or more, 60 wt% or more, 70 wt% or more, 80 wt% or more, 90 wt% or more, 99 wt% or more. In some embodiments, the silybin component (e.g., as described herein) has a weight percentage of silybin (e.g., amorphous (e.g., a-polymorphic) silybin) that is 99 wt% or less, 90 wt% or less, 80 wt% or less, 70 wt% or less, 60 wt% or less, 50 wt% or less, 40 wt% or less. In some embodiments, the silybin component (e.g., as described herein) has a weight percentage of silybin (e.g., amorphous (e.g., a-polymorphic) silybin) that is at least 80 wt%, at least 85 wt%, at least 90 wt%, at least 95 wt% or more.

[0076] In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has from 1 wt% to 100 wt% (e.g., up to 1 wt%, up to 10 wt%, up to 20 wt%, up to 30 wt%, up to 40 wt%, up to 50 wt%, up to 60 wt% or less) of a carrier (e.g., a carrier component including a carrier (e.g., an excipient) provided herein). In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a wt% of carrier (e.g., a carrier (e.g., an excipient) provided herein, etc.) that is 1 wt% or less, 10 wt% or less, 20 wt% or less, 30 wt% or less, 40 wt% or less, 50 wt% or less, 60 wt% or less. In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a wt% of carrier (e.g., a carrier component including a carrier (e.g., an excipient) provided herein) that is 60 wt% or more, 50 wt% or more, 40 wt% or more, 30 wt% or more, 20 wt% or more, 10 wt% or more, 1 wt% or more. In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a wt% of carrier (e.g., a carrier component including a carrier (e.g., an excipient) provided herein) that is up to 20 wt%, up to 15 wt%, up to 10 wt%, up to 5 wt% or less.

[0077] In some embodiments, the plurality of discrete particles have a carrier (e.g., a carrier component including a carrier provided herein (e.g., an excipient), etc.) of 1 wt% to 100 wt% (e.g., at most 1 wt%, at most 10 wt%, at most 20 wt%, at most 30 wt%, at most 40 wt%, at most 50 wt%, at most 60 wt% or less). In some embodiments, the plurality of discrete particles have a carrier (e.g., a carrier provided herein (e.g., an excipient), etc.) in a weight percentage of 1 wt% or less, 10 wt% or less, 20 wt% or less, 30 wt% or less, 40 wt% or less, 50 wt% or less, 60 wt% or less. In some embodiments, the plurality of discrete particles have a carrier (e.g., a carrier component including a carrier provided herein (e.g., an excipient), etc.) in a weight percentage of 60 wt% or more, 50 wt% or more, 40 wt% or more, 30 wt% or more, 20 wt% or more, 10 wt% or more, 1 wt% or more. In some embodiments, the plurality of discrete particles have a carrier (e.g., a carrier component including a carrier provided herein (e.g., an excipient), etc.) in a weight percentage of at most 20 wt%, at most 15 wt%, at most 10 wt%, at most 5 wt% or less.

[0078] In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a ratio of carrier (e.g., a carrier component) to silybin (e.g., a silybin component (e.g., an amorphous (e.g., a-polymorphic) silybin)) of 1:99 to about 99:1, about 1:99 to about 90:10, about 25:75 to about 75:25, about 40:60 to about 60:40, or about 80:20 to about 50:50. In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a ratio of carrier (e.g., a carrier component) to silybin (e.g., a silybin component (e.g., an amorphous (e.g., a-polymorphic) silybin)) of about 1:99, about 5:95, about 10:90, about 15:85, or about 20:80.

[0079] In some embodiments, a plurality of discrete particles (e.g., an amorphous (e.g., a-polymorphic) silybin composition) have a ratio of carrier (e.g., carrier constituent) to silybin (e.g., silybin constituent (e.g., amorphous (e.g., a-polymorphic) silybin)). In some embodiments, one or more discrete particles of the plurality of discrete particles (e.g., an amorphous (e.g., a-polymorphic) silybin composition) have a ratio of carrier (e.g., carrier constituent) to silybin (e.g., silybin constituent (e.g., amorphous (e.g., a-polymorphic) silybin)). In some embodiments, each particle of the plurality of discrete particles (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a ratio of carrier (e.g., carrier constituent) to silybin (e.g., silybin constituent (e.g., amorphous (e.g., a-polymorphic) silybin)). In some embodiments, the carrier-to-silybin ratio is from about 1:99 to about 99:1, from about 1:99 to about 90:10, from about 25:75 to about 75:25, from about 40:60 to about 60:40, or from about 80:20 to about 50:50. In some embodiments, the composition (e.g., an amorphous (e.g., a-polymorphic) silybin composition) has a carrier (e.g., carrier constituent) to silybin (e.g., silybin constituent (e.g., amorphous (e.g., a-polymorphic) silybin)) ratio of about 1:99, about 5:95, about 10:90, about 15:85, or about 20:80. In some examples, the carrier-to-silybin ratio is an average ratio (e.g., an average ratio calculated using each of the plurality of discrete particles).

[0080] In some examples, the amorphous solid has better pharmacokinetic and / or pharmacodynamic properties (e.g., solubility) than the crystalline solid. In some examples, amorphous (e.g., a-polymorphic) silybin has better pharmacokinetic and / or pharmacodynamic properties (e.g., solubility, bioavailability, etc.) than crystalline silybin. In some examples, amorphous (e.g., a-polymorphic) silybin is useful for providing a low dose of silybin (e.g., to an individual in need thereof). In some examples, an amorphous solid dispersion (ASD) increases the stability of the amorphous compound. In some examples, the ASD is an amorphous composition of an active agent and a polymer. In some examples, the pH of amorphous (e.g., polymorphic) silybin increases the stability of the amorphous composition. In some examples, the purity of amorphous (e.g., polymorphic) silybin increases the stability of the amorphous composition.

[0081] In some embodiments, the compositions provided herein (e.g., an amorphous (e.g., a-polymorphic) silybin composition) comprise an amorphous solid dispersion (ASD). In some embodiments, the compositions provided herein (e.g., an amorphous (e.g., a-polymorphic) silybin composition) are an ASD.

[0082] In some embodiments, discrete particles of a plurality of discrete particles (e.g., one or more discrete particles) comprise an ASD. In some embodiments, at least one discrete particle of a plurality of discrete particles comprises an ASD. In some embodiments, a plurality of discrete particles (e.g., provided herein) comprise an ASD. In some embodiments, a plurality of discrete particles (e.g., provided herein) are an ASD.

[0083] In some embodiments, provided herein are a plurality of discrete particles comprising a carrier component comprising at least one carrier and a silybin component comprising amorphous (e.g., a-polymorphic) silybin (determined by, for example, XRPD, DSC, melting point, SSNMR, or polarized microscopy). In some embodiments, the composition comprises one or more of the discrete particles of the plurality of discrete particles. In some embodiments, the composition comprises the plurality of discrete particles. In some embodiments, each of the plurality of discrete particles comprises at least a portion of the carrier component. In some embodiments, one or more of the plurality of discrete particles comprises at least a portion of the carrier component. In some embodiments, each of the plurality of discrete particles comprises at least a portion of the silybin component. In some embodiments, one or more of the plurality of discrete particles comprises at least a portion of the silybin component. In some embodiments, each of the plurality of discrete particles independently comprises at least a portion of the carrier component. In some embodiments, each of the plurality of discrete particles independently comprises at least a portion of the silybin component. In some embodiments, each of the plurality of discrete particles independently comprises at least a portion of the carrier component and at least a portion of the silybin component.

[0084] In some embodiments, at least one of the discrete particles of the plurality of discrete particles comprises at least one discrete domain embedded in a matrix. In some embodiments, each of at least one of the discrete particles of the plurality of discrete particles comprises at least one discrete domain embedded in a matrix.

[0085] In some embodiments, at least one discrete particle of the plurality of discrete particles comprises at least one discrete domain (e.g., comprising at least a portion of a silibinin component and / or at least a portion of a carrier component). In some embodiments, each of the discrete particles of the plurality of discrete particles comprises at least one discrete domain (e.g., comprising at least a portion of a silibinin component and / or at least a portion of a carrier component). In some embodiments, a discrete particle (e.g., comprising a discrete domain) comprises a portion of amorphous (e.g., a-polymorphic) silibinin (e.g., a silibinin component). In some embodiments, a discrete particle (e.g., comprising a discrete domain) comprises a portion of a carrier (e.g., a carrier component). In some embodiments, a discrete particle (e.g., comprising a discrete domain) comprises a portion of a silibinin component and a portion of a carrier component. In some embodiments, a discrete particle (e.g., comprising a discrete domain) comprises an additional agent (e.g., provided elsewhere herein).

[0086] In some embodiments, at least one discrete particle of the plurality of discrete particles comprises a plurality of discrete domains (e.g., each discrete domain independently comprises at least a portion of amorphous (e.g., a-polymorphic) silibinin (e.g., a silibinin component) and / or a carrier (e.g., a carrier component)). In some embodiments, each discrete domain independently comprises at least a portion of a silibinin component. In some embodiments, each discrete domain independently comprises at least a portion of a carrier component. In some embodiments, each discrete domain independently comprises at least a portion of a silibinin component and at least a portion of a carrier component.

[0087] In some embodiments, at least one discrete particle of a plurality of discrete particles comprises a matrix (e.g., comprising at least a portion of a silybin component and / or a carrier component). In some embodiments, each of the discrete particles of the plurality of discrete particles comprises a matrix (e.g., comprising at least a portion of a silybin component and / or at least a portion of a carrier component). In some embodiments, the matrix (e.g., comprising at least one discrete domain) comprises a portion of amorphous (e.g., a-polymorphic) silybin (e.g., a silybin component). In some embodiments, the matrix (e.g., comprising at least one discrete domain) comprises a portion of a carrier (e.g., a carrier component). In some embodiments, the matrix (e.g., comprising at least one discrete domain) comprises a portion of a silybin component and a portion of a carrier component. In some embodiments, the matrix (e.g., comprising at least one discrete domain) comprises an additional agent (e.g., provided elsewhere herein).

[0088] In some embodiments, at least one discrete particle of the plurality of discrete particles comprises a plurality of matrices (e.g., each matrix independently comprises at least a portion of amorphous (e.g., a-polymorphic) silybin (e.g., a silybin component) and / or a carrier (e.g., a carrier component)). In some embodiments, each matrix independently comprises at least a portion of a silybin component. In some embodiments, each matrix independently comprises at least a portion of a carrier component. In some embodiments, each matrix independently comprises at least a portion of a silybin component and a carrier component.

[0089] In some embodiments, the matrix comprises a portion of a carrier component and the discrete domain comprises a portion of a silybin component (e.g., amorphous (e.g., a-polymorphic) silybin).

[0090] In some embodiments, the matrix comprises a part of the shilocin component and the distinct domain comprises a part of the carrier component.

[0091] In some embodiments, at least one of the plurality of distinct particles comprises a matrix. In some embodiments, the matrix comprises a carrier component. In some embodiments, the matrix comprises a part of the carrier component. In some embodiments, the matrix comprises a shilocin component. In some embodiments, the matrix comprises a part of the shilocin component. In some embodiments, the matrix comprises a carrier component and a shilocin component. In some embodiments, the matrix comprises a part of the carrier component and a part of the shilocin component. In some embodiments, the matrix comprises an additional agent. In some embodiments, the matrix comprises a part of the additional agent.

[0092] In some embodiments, at least one of the plurality of distinct particles comprises a distinct domain and a matrix. In some embodiments, the distinct particle of the plurality of distinct particles comprises a distinct domain embedded in the matrix. In some embodiments, each distinct particle of the plurality of distinct particles comprises a distinct domain and a matrix. In some embodiments, in the distinct particle of the plurality of distinct particles, the distinct domain is outside the matrix. In some embodiments, the distinct particle comprises a matrix within the distinct domain. In some embodiments, the distinct particle comprises a distinct domain mixed with the matrix.

[0093] In some embodiments, the matrix comprises shiloshbin (e.g., a shiloshbin component), for example, amorphous (e.g., a-polymorphic) shiloshbin, and the separate domain comprises a carrier (e.g., a carrier component). In some embodiments, the matrix comprises a portion of shiloshbin and the separate domain comprises a portion of the carrier. In some embodiments, the matrix comprises the carrier and the separate domain comprises shiloshbin. In some embodiments, the matrix comprises a portion of the carrier and the separate domain comprises a portion of shiloshbin.

[0094] In some embodiments, the ASD comprises an amorphous solid solution or a semi-solid solution. In some examples, the amorphous solid solution or semi-solid solution comprises a carrier (e.g., a carrier component (e.g., an amorphous carrier component)) mixed with shiloshbin (e.g., amorphous (e.g., a-polymorphic) shiloshbin (e.g., a shiloshbin component)).

[0095] In some embodiments, the ASD comprises shiloshbin (e.g., amorphous (e.g., a-polymorphic) shiloshbin) in a shiloshbin-rich phase and a carrier ((e.g., a carrier component) e.g., an amorphous carrier component) in a carrier-rich phase (e.g., a dispersion). In some embodiments, the dispersion is a solid or semi-solid dispersion.

[0096] In some embodiments, at least one (e.g., one or more) of the plurality of separate particles comprises a heterogeneous mixture of components (e.g., each component is in one or more (e.g., two) different phases (e.g., a dispersion (e.g., a solid or semi-solid))).

[0097] In some embodiments, at least one (e.g., one or more) of the plurality of separate particles comprises a solid dispersion of shiloshbin (e.g., a shiloshbin component) in a carrier component. In some embodiments, at least one of the plurality of separate particles comprises a semi-solid dispersion of shiloshbin in a carrier component.

[0098] In some examples, the dispersion is a solid dispersion. In some embodiments, the dispersion is a semi-solid dispersion. The dispersion (e.g., solid or semi-solid) can be a dispersion of one or more active ingredients (e.g., silibinin) in a carrier (e.g., carrier component). In some embodiments, the dispersion (e.g., solid or semi-solid) comprises silibinin (e.g., silibinin component (e.g., amorphous (e.g., a-polymorphic) silibinin)). In some embodiments, the dispersion (e.g., solid or semi-solid) comprises a carrier component. In some embodiments, the dispersion (e.g., solid or semi-solid) comprises silibinin in a carrier component. In some embodiments, the dispersion (e.g., solid or semi-solid) comprises a carrier (e.g., carrier component) in silibinin (e.g., silibinin component). In some embodiments, the solid dispersion is a powder (e.g., loose powder and / or compressed powder).

[0099] In some embodiments, the semi-solid dispersion is selected from the group consisting of gels (e.g., hydrogels), ointments, creams, lotions, emulsions (e.g., microemulsions), and pastes.

[0100] In some examples, the dispersion is a liquid dispersion. The liquid dispersion can be a dispersion of one or more active ingredients (e.g., silibinin) in a carrier (e.g., carrier component). In some embodiments, the liquid dispersion comprises silibinin (e.g., amorphous (e.g., a-polymorphic) silibinin (e.g., silibinin component)). In some embodiments, the liquid dispersion comprises a carrier component. In some embodiments, the liquid dispersion comprises silibinin in a carrier component. In some embodiments, the liquid dispersion comprises a carrier (e.g., carrier component) in silibinin (e.g., silibinin component). In some embodiments, the liquid dispersion is selected from the group consisting of solutions, dispersions, suspensions, and emulsions.

[0101] In some embodiments, at least one (e.g., one or more) of the plurality of discrete particles comprises a mixture containing two or more substances in the same phase (e.g., a solution (e.g., a solid solution or a semi-solid solution)).

[0102] In some embodiments, at least one (e.g., one or more) of the plurality of discrete particles comprises a solid solution of silybin in a carrier component. In some embodiments, at least one of the plurality of discrete particles comprises a semi-solid solution of silybin in a carrier component.

[0103] The solution (e.g., solid or semi-solid) can be a solution of one or more active ingredients (e.g., silybin) in a carrier (e.g., a carrier component). In some embodiments, the solution (e.g., solid or semi-solid) comprises silybin ((e.g., silybin component (e.g., amorphous (e.g., a-polymorphic) silybin)). In some embodiments, the solution (e.g., solid or semi-solid) comprises a carrier component. In some embodiments, the solution (e.g., solid or semi-solid) comprises silybin in a carrier component. In some embodiments, the solution (e.g., solid or semi-solid) comprises a carrier (e.g., a carrier component) in silybin (e.g., a silybin component). In some embodiments, the solid solution is a powder (e.g., a loose powder and / or a compressed powder). In some embodiments, the semi-solid solution is selected from the group consisting of a gel (e.g., a hydrogel), an ointment, a cream, a lotion, an emulsion (e.g., a microemulsion), and a paste.

[0104] In some examples, the solution is a liquid solution. The liquid solution can be a solution of one or more active ingredients (e.g., silibinin) in a carrier (e.g., a carrier component). In some embodiments, the liquid solution contains silibinin (e.g., a silibinin component (e.g., amorphous (e.g., a-polymorphic) silibinin)). In some embodiments, the liquid solution contains a carrier component. In some embodiments, the liquid solution contains silibinin in a carrier component. In some embodiments, the liquid solution contains a carrier (e.g., a carrier component) in silibinin (e.g., a silibinin component).

[0105] In some embodiments, the composition contains a drug. In some embodiments, the plurality of discrete particles contain a drug. In some embodiments, the drug contains a carrier (e.g., a carrier component). In some embodiments, the drug contains an additional drug. In some embodiments, the drug contains an additional drug and a carrier. In some embodiments, the plurality of discrete particles are within the drug. In some embodiments, the drug is within the plurality of discrete particles. In some embodiments, the plurality of discrete particles are adjacent to the drug.

[0106] In some embodiments, the composition contains one or more active agents. In some embodiments, each of the plurality of discrete particles contains one or more active agents. In some embodiments, one or more of the plurality of discrete particles contain one or more active agents. In some embodiments, the one or more active agents are silibinin (e.g., amorphous (e.g., a-polymorphic) silibinin (e.g., a silibinin component)). In some embodiments, the one or more active agents are an additional drug. In some embodiments, the composition contains an additional drug. In some embodiments, at least one of the plurality of discrete particles contains an additional drug. In some embodiments, each of the plurality of discrete particles contains an additional drug. In some embodiments, the matrix contains and an additional drug. In some embodiments, the discrete domain contains an additional drug.

[0107] In some embodiments, the additional agent is a 5HT receptor agonist (e.g., other than silibinin), a stimulant, an antihistamine, an antiemetic, an antidepressant, an anti-inflammatory agent, a growth factor, a lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, a 5HT receptor antagonist, an anxiolytic, or a mood stabilizer, and combinations thereof.

[0108] In some embodiments, one or more (i.e., at least one) of the plurality of discrete particles has a ratio of carrier constituent to silibinin constituent (e.g., amorphous (e.g., a-polymorphic) silibinin) of about 1:99 to about 99:1 (e.g., on average), about 1:99 to about 90:10 (e.g., on average), about 25:75 to about 75:25 (e.g., on average), about 40:60 to about 60:40 (e.g., on average), or about 80:20 to about 50:50 (e.g., on average). In some embodiments, one or more (i.e., at least one) of the plurality of discrete particles has a ratio of carrier (e.g., carrier constituent) to silibinin (e.g., silibinin constituent (e.g., amorphous (e.g., a-polymorphic) silibinin)) of about 1:99 (e.g., on average), about 5:95 (e.g., on average), about 10:90 (e.g., on average), about 15:85 (e.g., on average), or about 20:80 (e.g., on average).

[0109] In some embodiments, each distinct particle of the plurality of distinct particles has a ratio of carrier component to silybin component (e.g., amorphous (e.g., a-polymorphic) silybin) of from about 1:99 to about 99:1 (e.g., on average), from about 1:99 to about 90:10 (e.g., on average), from about 25:75 to about 75:25 (e.g., on average), from about 40:60 to about 60:40 (e.g., on average), or from about 80:20 to about 50:50 (e.g., on average). In some embodiments, each distinct particle of the plurality of distinct particles has a ratio of carrier (e.g., carrier component) to silybin (e.g., silybin component (e.g., amorphous (e.g., a-polymorphic) silybin)) of about 1:99 (e.g., on average), about 5:95 (e.g., on average), about 10:90 (e.g., on average), about 15:85 (e.g., on average), or about 20:80 (e.g., on average).

[0110] Any particle provided herein can be of any suitable size (e.g., large or small) and can be prepared by any of the methods provided herein (e.g., hot melt extrusion, spray drying, wet / granulation and fluidization, microwave or tray drying, freeze drying, drum drying, precipitation (e.g., crash precipitation), supercritical fluidization, etc.).

[0111] In some embodiments, for example, the content of a composition such as at least a portion of the carrier component and / or at least a portion of the silybin component (in the composition) is determined by a method (e.g., provided herein) for characterizing the order (e.g., structure) of a composition (e.g., a pharmaceutical) such as provided elsewhere herein. In some embodiments, the content (e.g., amount, ratio, weight %) of silybin (component) (e.g., amorphous (e.g., a-polymorphic) silybin) in the composition is determined using a method (e.g., provided herein) for characterizing the order (e.g., structure) of a composition (e.g., a pharmaceutical) such as provided elsewhere herein. In some examples, a portion of the silybin component and / or the carrier component comprises silybin (e.g., amorphous (e.g., a-polymorphic) silybin).

[0112] In some embodiments, the content (e.g., amount, ratio, weight %) of at least a portion of the carrier component and / or at least a portion of the silybin component in the composition is determined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) (e.g., modulated DSC), solid state nuclear magnetic resonance (SSNMR), melting point, polarized light microscopy, or any combination thereof. In some embodiments, the structural order and / or disruption of the silybin (e.g., amorphous) component is determined by XRPD, DSC, SSNMR, melting point, or polarized light microscopy, or any combination thereof.

[0113] In some examples, the portion (e.g., amount, ratio, weight %) of the carrier component and / or the portion of the silybin component in the composition is determined by spectroscopy (e.g., Raman, infrared, or near infrared).

[0114] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a pharmaceutical composition for treating (e.g., curing or healing) or alleviating (e.g., reducing or making less severe) a disease or disorder, or a pharmaceutical composition related to a disease or disorder (e.g., a symptom (e.g., physical or mental), biomarker, or other sign (e.g., indication (e.g., diagnostic, pathological, prognostic, or historical))).

[0115] In some embodiments, the pharmaceutical composition is suitable for administration (e.g., oral) to an individual (e.g., rodents, monkeys, humans, etc. (e.g., those in need thereof)).

[0116] In some embodiments, the pharmaceutical composition is suitable for enteral (e.g., oral, rectal, etc.) administration. In some embodiments, the pharmaceutical composition is suitable for oral administration. Suitable forms of pharmaceutical compositions for oral administration include tablets, capsules, orally designated formulations (e.g., tablets and films), sublingual formulations, buccal medications, oral liquids, eye, vaginal, formulations, or combinations thereof.

[0117] In some embodiments, the composition is prepared using any suitable technique (e.g., for forming an amorphous composition and / or ASD). In some examples, the technique produces an amorphous composition (e.g., an amorphous solid dispersion or amorphous (e.g., a-polymorph) silybin). In some embodiments, the technique produces a plurality of discrete particles that are amorphous. In some embodiments, the technique includes spray drying (e.g., spray dried composition and / or spray dried particles), hot melt extrusion (e.g., hot melt extruded composition and / or hot melt extruded particles), freeze drying (e.g., freeze dried composition and / or freeze dried particles), melt quenching (e.g., melt quenched composition and / or melt quenched particles), ball milling (e.g., ball milled composition and / or ball milled particles), cryogrinding (e.g., cryoground composition and / or cryoground particles), solvent removal (e.g., solvent removed composition and / or solvent removed particles), precipitation (e.g., precipitated composition and / or precipitated particles), drum drying (e.g., drum dried composition and / or drum dried particles), pulse combustion drying (e.g., pulse combustion dried composition and / or pulse combustion dried particles), crash precipitation (e.g., crash precipitated composition and / or crash precipitated particles), supercritical fluidization (e.g., supercritical fluidized composition and / or supercritical fluidized particles), particle drying after wet granulation (e.g., fluid bed, microwave, or tray drying), or combinations thereof.

[0118] In some embodiments, the composition is selected from the group consisting of a spray dried composition, a freeze dried composition, a drum dried composition, a hot melt extruded composition, a precipitated composition (e.g., crash precipitation), a supercritical fluidized composition, a wet granulation dried composition, and a pulse combustion dried composition.

[0119] In some embodiments, the composition is a spray dried composition (e.g., produced by rapidly drying a liquid or slurry with a hot gas or by emulsification / solvent removal).

[0120] In some embodiments, the composition is a hot melt extrusion composition (e.g., produced by applying heat and pressure to a polymer to dissolve the polymer and then extruding the polymer from an orifice).

[0121] In some embodiments, the composition is a spray-dried composition or a hot melt extrusion composition.

[0122] In some embodiments, the composition is a drum-dried composition (e.g., produced by rotating the components of the composition within a drum over a period of time to dry the liquid within the components).

[0123] In some embodiments, the composition is a crash precipitation composition (e.g., produced by separating solid particles from a liquid (e.g., a precipitation composition)).

[0124] In some embodiments, the composition is a supercritical fluidized composition (e.g., produced by fluidizing the composition in a supercritical fluid bed with a supercritical fluid (e.g., any substance that is at a temperature and pressure above its critical point but below the pressure required to compress the substance to a solid)).

[0125] In some embodiments, the composition is a pulse combustion dried composition (e.g., produced by using one or more pulse combustors to generate high temperature and high speed pulse jets to dry the components of the composition).

[0126] In some embodiments, any one of the compositions provided herein (e.g., an (e.g., synthetic) a-polymorphic composition or an amorphous silybin composition) is stable for any suitable period. As used herein, "stability" can refer to chemical or physical stability.

[0127] In some embodiments, any one of the compositions provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) is chemically stable for any suitable period. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) is chemically stable for at least one week (e.g., at least two weeks, at least one month, at least two months, at least three months, at least four months, at least six months) under ambient conditions and the like. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) is chemically stable for at least one month under ambient conditions and the like. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) is chemically stable for up to one year (e.g., up to six months, up to four months, up to two months, up to one month) under ambient conditions and the like. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silybin composition) is chemically stable for about one week to about one year under ambient conditions and the like. In some embodiments, chemical stability can refer to at least 99.5% (e.g., at least 99%, at least 98%, at least 97%, at least 95%, at least 90%) of silybin remaining (e.g., not decomposing) after a certain period. In some embodiments, at least 95% of silybin remains (e.g., does not decompose) after one month under ambient conditions and the like.

[0128] Silibinin has a tendency to crystallize when prepared in its amorphous form. In some embodiments, any one of the compositions provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) is physically stable over any suitable amount of time. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) is physically stable for at least 1 week (e.g., at least 2 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 6 months) under ambient conditions and the like. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) is physically stable for up to 1 year (e.g., up to 6 months, up to 4 months, up to 2 months, up to 1 month, up to 2 weeks). In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) is physically stable for about 1 week to about 1 year under ambient conditions and the like. In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) is stable for at least 1 month under ambient conditions and the like. Physical stability can refer to the absence of a phase transition such as the transition from the amorphous to the crystalline phase or the absence of solid hydration. In some embodiments, physical stability can be evaluated by XRPD as described in Example 3 (Figure 3). In other embodiments, physical stability can be determined by melting point, DSC (e.g., modulated DSC), SSNMR, or polarized light microscopy. In some embodiments, physical stability is evaluated by melting point. In some embodiments, physical stability is evaluated by DSC (e.g., modulated DSC). In some embodiments, physical stability is evaluated by SSNMR. In some embodiments, physical stability is evaluated by polarized light microscopy as described, for example, in Example 3.

[0129] In some embodiments, any one of the compositions provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) does not contain a carrier (e.g., does not contain a polymer) and does not contain crystalline silibinin completely for at least one week (e.g., at least two weeks, at least one month, at least two months, at least four months, at least six months). In some embodiments, any one of the compositions provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) does not contain a carrier (e.g., does not contain a polymer) and does not contain crystalline silibinin completely after up to one year (e.g., up to six months, up to four months, up to two months, up to one month). In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) does not contain a carrier (e.g., does not contain a polymer) and does not contain crystalline silibinin completely after about one week to about one year. In some embodiments, the composition provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) does not contain a carrier (e.g., does not contain a polymer) and does not contain silibinin completely for at least four weeks, as described in Example 3. In some embodiments, the composition does not contain crystalline silibinin completely after any suitable (e.g., storage) period at room temperature. In other embodiments, the composition does not contain crystalline silibinin completely after any suitable (e.g., storage) period at low temperature. In some embodiments, the composition does not contain crystalline silibinin completely after any suitable (e.g., storage) period at high temperature.

[0130] In some embodiments, any one of the compositions provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) does not contain a carrier (e.g., does not contain a polymer) and is substantially free of crystalline silibinin for at least one week (e.g., at least two weeks, at least one month, at least two months, at least four months, at least six months). In some embodiments, any one of the compositions provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) does not contain a carrier (e.g., does not contain a polymer) and is substantially free of crystalline silibinin after up to one year (e.g., up to six months, up to four months, up to two months, up to one month). In some embodiments, the composition (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) does not contain a carrier (e.g., does not contain a polymer) and is substantially free of crystalline silibinin about one week to about one year later. In some embodiments, the compositions provided herein (e.g., (e.g., synthetic) a-polymorphic composition or amorphous silibinin composition) do not contain a carrier (e.g., do not contain a polymer) and are substantially free of silibinin for at least four weeks, as described in Example 3. In some embodiments, the composition is substantially free of crystalline silibinin after any suitable (e.g., storage) period at room temperature. In other embodiments, the composition is substantially free of crystalline silibinin after any suitable (e.g., storage) period at low temperature. In some embodiments, the composition is substantially free of crystalline silibinin after any suitable (e.g., storage) period at high temperature.

[0131] In some embodiments, synthetic a-polymorphic silybin is provided that is substantially free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized microscopy) (e.g., the XRPD scan is free of reflections or peaks). In some embodiments, the synthetic a-polymorphic silybin contains no single impurity in excess of 2% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.15%), and has a chemical purity of at least 95% (e.g., at least 95%, 96%, 97%, 98%, 99%, or 99.5%, and all values in between), as determined by, for example, high performance liquid chromatography (HPLC) or reverse phase HPLC. In some embodiments, the synthetic a-polymorphic silybin has a chemical purity of at least 98%. In some embodiments, the synthetic a-polymorphic silybin is concentrated. In some embodiments, the synthetic a-polymorphic silybin is spray-dried a-polymorphic silybin. In some embodiments, the synthetic a-polymorphic silybin is lyophilized a-polymorphic silybin.

[0132] Production of amorphous silybin In some embodiments, a method for generating any one of the compositions provided herein is provided herein. In some embodiments, a method for generating any amorphous silybin (e.g., a silybin constituent) is provided herein. In some embodiments, a method for generating any a-polymorphic silybin composition provided herein is provided herein. In some embodiments, a method for generating amorphous (e.g., a-polymorphic) silybin comprises: (i) providing (e.g., synthesizing) a silybin constituent; (ii) combining the silybin constituent with a carrier constituent, wherein the carrier constituent comprises at least one carrier for generating a silybin-carrier composition; and (iii) treating the silybin-carrier composition to generate one or more particles (e.g., an amorphous composition) comprising amorphous (e.g., a-polymorphic) silybin (e.g., a constituent) and the carrier constituent. In some embodiments, providing silybin (e.g., a silybin constituent) comprises synthesizing silybin (e.g., amorphous (e.g., a-polymorphic) silybin). In some examples, providing silybin (e.g., a silybin constituent) comprises synthesizing silybin (e.g., amorphous (e.g., a-polymorphic) silybin) without generating a crystalline (e.g., silybin) intermediate (a-polymorphic silybin). In some embodiments, not generating a crystalline (e.g., silybin) intermediate means avoiding the generation of silybin in crystalline form.

[0133] In some embodiments, a silybin-carrier composition (e.g., any of the compositions described herein) is generated by combining (e.g., mixing, folding, layering, etc.) silybin (e.g., a silybin constituent (e.g., amorphous (e.g., a-polymorphic) silybin)) and a carrier (e.g., a carrier constituent).

[0134] In some embodiments, treating the silibinin-carrier composition comprises generating one or more particles comprising silibinin (e.g., a silibinin component (e.g., amorphous (e.g., a-polymorphic) silibinin)) and a carrier (e.g., a carrier component (e.g., comprising at least one carrier)) (e.g., generating a composition (e.g., an amorphous composition)).

[0135] In some embodiments, the silibinin component comprises silibinin. In some embodiments, the silibinin component comprises amorphous (e.g., a-polymorphic) silibinin.

[0136] In some embodiments, methods are provided herein for generating an amorphous composition comprising silibinin (e.g., amorphous (e.g., a-polymorphic) silibinin). In some embodiments, a method for generating an amorphous composition comprising silibinin comprises: a.) synthesizing a silibinin component; and b.) generating an amorphous composition comprising the silibinin component. In some examples, synthesizing the silibinin component comprises synthesizing silibinin (e.g., amorphous (e.g., a-polymorphic) silibinin) without generating a crystalline (e.g., silibinin) intermediate. In some embodiments, generating the amorphous composition is lyophilization.

[0137] In some embodiments, a method for generating amorphous (e.g., a-polymorphic) silibinin comprises treating a silibinin-carrier composition to generate amorphous (e.g., a-polymorphic) silibinin (e.g., an ASD). In some embodiments, a method for generating one or more particles comprises treating (e.g., silibinin (e.g., a silibinin component) and / or a carrier (e.g., a carrier component)).

[0138] In some embodiments, the silibinin component is the sole component of the amorphous composition.

[0139] In some embodiments, the processing (e.g., generating) is selected from the group consisting of spray drying, freeze drying, drum drying, precipitation (e.g., crash precipitation), hot melt extrusion, supercritical fluidization, and pulse combination drying, or combinations thereof. In some embodiments, the processing is selected from the group consisting of spray drying, wet granulation / fluid drying, wet granulation / microwave drying, wet granulation / tray drying, freeze drying (e.g., lyophilization), drum drying, precipitation (e.g., crash precipitation), hot melt extrusion, supercritical fluidization, and pulse combination drying, or combinations thereof.

[0140] In some embodiments, provided herein is a method of making any one of the compositions provided herein. In some embodiments, provided herein is a method of making any one of the synthetic a-polymorphic silybin provided herein. In some embodiments, provided herein is an amorphous (e.g., a-polymorphic) silybin composition provided herein. In some embodiments, provided herein is a method of making a synthetic a-polymorph silybin composition. In some embodiments, provided herein is a method of making any one of the silybin provided herein. In some embodiments, provided herein is an amorphous (e.g., a-polymorphic) silybin provided herein. In some embodiments, provided herein is a method of making synthetic a-polymorphic silybin. In some embodiments, at least 50% (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 99%, at least 99.5%) of the composition is composed of amorphous (e.g., a-polymorphic) silybin. In some embodiments, up to 99.5% (e.g., up to 99%, up to 97%, up to 95%, up to 80%, up to 70%) of the composition is composed of amorphous (e.g., a-polymorphic) silybin. In some embodiments, about 50% to about 99.5% of the composition is composed of amorphous (e.g., a-polymorphic) silybin.

[0141] In some embodiments, the method includes the synthesis of benzyl {3-[2-(benzyldimethylammonio)ethyl]-1H-indol-4-yl} phosphate according to Schemes 1-3 of Example 2 and the synthesis of amorphous (e.g., a-polymorphic) silibinin according to Scheme 4 of Example 2. In some embodiments, the method includes the synthesis of protected silibinin (e.g., benzyl {3-[2-(benzyldimethylammonio)ethyl]-1H-indol-4-yl} phosphate) by any known method of the prior art (e.g., Sherwood et al. Synthesis 2020, 52, 688-694, Hofmann, A. et al. Helv. Chim. Acta 1959, 42, 1557, Nichols, D. E.; Frescas, S. Synthesis, 1999, 935, Kargbo et al. ACS Omega 2020, 5, 16959-16966) and the synthesis of amorphous (e.g., a-polymorphic) silibinin according to Scheme 4 of Example 2. In some embodiments, the method includes liquid-liquid extraction for purifying amorphous (e.g., a-polymorphic) silibinin. In some examples, the pH of the liquid-liquid extraction increases the purity of amorphous (e.g., a-polymorphic) silibinin. In some examples, the pH of the liquid-liquid extraction increases the stability of amorphous (e.g., a-polymorphic) silibinin. In some examples, the purity of amorphous (e.g., a-polymorphic) silibinin increases the stability of the amorphous composition.

[0142] In one embodiment, a method of making synthetic a-polymorphic silibinin is provided, the method comprising a. providing benzyl {3-[2-(benzyldimethylammonio)ethyl]-1H-indol-4-yl} phosphate; b. deprotecting benzyl {3-[2-(benzyldimethylammonio)ethyl]-1H-indol-4-yl} phosphate in a reaction solvent to provide silibinin; c. extracting silibinin from the reaction solvent into an aqueous medium and washing the aqueous medium with an organic solvent; d. concentrating the aqueous medium containing silibinin; e. collecting amorphous (e.g., a-polymorphic) silybin.

[0143] In some embodiments, the method includes providing protected silybin. In some embodiments, the protected silybin is represented by the following structure.

[0144]

Chemical formula

[0145] In some embodiments, each R is independently hydrogen or a protecting group. In some embodiments, both Rs are hydrogen. In some embodiments, both Rs are protecting groups. In some embodiments, one R is hydrogen and the other R is a protecting group. In some embodiments, the protecting group includes benzene. In some embodiments, the protecting group includes methylbenzene.

[0146] In some embodiments, the synthesis of protected silybin is described in Example 2. In some examples, the synthesis of protected silybin, as described in Example 2 and Schemes 1-3, includes synthesizing 6(3-[2-(dimethylamino)2-oxoacetyl]-1H-indole-4-ylacetate from 1H-indole-4-ylacetate, followed by the synthesis of silosine, followed by the synthesis of protected silybin.

[0147] In some embodiments, the method includes deprotecting the protected silybin. In some embodiments, the method includes deprotecting the protected silybin in a reaction solvent. In some embodiments, the reaction solvent includes alcohol. In some embodiments, the alcohol may include any suitable alcohol according to those skilled in the art. In some embodiments, the alcohol includes methanol, ethanol, tert-butanol, butanol, pentanol, or hexanol. In some embodiments, the alcohol includes methanol. In some embodiments, deprotecting includes hydrogenolysis.

[0148] In some embodiments, the method includes extracting shiloshibin from a reaction solvent. In some embodiments, the method includes extracting shiloshibin into an aqueous medium. In some embodiments, the method includes extracting shiloshibin from a reaction solvent into an aqueous medium. In some embodiments, the method includes washing the aqueous medium with an organic solvent. In some embodiments, the method includes extracting shiloshibin from a reaction solvent into an aqueous medium and washing the aqueous medium with an organic solvent. In some embodiments, the reaction solvent may be dissolved in the aqueous medium. In some embodiments, the reaction solvent may be immiscible with the aqueous medium. In some embodiments, the reaction solvent may be exposed to the aqueous medium before being exposed to the organic solvent.

[0149] In some embodiments, in any of the methods provided herein, the organic solvent includes any suitable organic solvent for extracting shiloshibin. In some embodiments, the organic solvent includes a halocarbon. In some embodiments, the organic solvent includes dichloromethane.

[0150] In some embodiments, in any of the methods provided herein, the aqueous medium has a pH of from about 8 to about 10. In some embodiments, in any of the methods provided herein, the aqueous medium has a pH of from about 7 to about 11. In some embodiments, in any of the methods provided herein, the aqueous medium has a pH of about 9. In some embodiments, in any of the methods provided herein, the aqueous medium has a pH of about 8.5. In some embodiments, in any of the methods provided herein, the aqueous medium has a pH of about 9.5. In some embodiments, in any of the methods provided herein, the aqueous medium has a pH of about 8. In some embodiments, in any of the methods provided herein, the aqueous medium has a pH of about 10. In some embodiments, the choice of pH can improve the extraction of shirosibirine into the aqueous layer. In some embodiments, a pH of about 9 can be important for extracting shirosibirine into the aqueous layer.

[0151] In some embodiments, the methods provided herein include concentrating the aqueous medium. In some embodiments, the methods provided herein include partially concentrating the aqueous medium. In some embodiments, the methods provided herein include completely concentrating the aqueous medium. In some embodiments, concentrating includes spray drying such as spray drying provided elsewhere herein. In some embodiments, concentrating includes spray drying as described in Example 3. In some embodiments, concentrating includes freeze drying such as freeze drying provided elsewhere herein. In some embodiments, concentrating includes freeze drying as described in Example 3. In some examples, the concentrated shirosibirine product is stable for at least one week as described in Example 3.

[0152] In some embodiments, the methods provided herein include collecting the amorphous solid, such as after concentrating the aqueous medium.

[0153] In some embodiments, at any point of the methods provided herein, the silybin is not in a crystalline state.

[0154] In some embodiments, the methods provided herein (e.g., generating) include lyophilization. In some embodiments, concentration includes lyophilization. In some embodiments, lyophilization is performed in the absence of a carrier material. In some embodiments, lyophilization is performed in the absence of a polymer. In some embodiments, the absence of a polymer includes lyophilizing amorphous (e.g., a-polymorphic) silybin without a carrier (e.g., a polymer). In some embodiments, the absence of a polymer includes lyophilizing amorphous (e.g., a-polymorphic) silybin with less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a carrier (e.g., a polymer). In some embodiments, lyophilization is performed in the presence of one or more sugars such as those described elsewhere herein. In some embodiments, the sugar includes mannitol and / or trehalose. In some embodiments, the sugar includes mannitol. In some embodiments, the sugar includes trehalose. In some embodiments, when lyophilization is performed in the presence of a sugar, the silybin-to-sugar ratio is from about 90:10 to about 10:90, as described in Example 3. In some embodiments, the silybin-to-sugar ratio is 50:50. In some embodiments, the silybin-to-sugar ratio is 25:75. In some embodiments, the silybin-to-sugar ratio is 75:25.

[0155] In some embodiments, the lyophilization provided herein includes a starting temperature of approximately room temperature. In some embodiments, the lyophilization provided herein includes cooling the temperature of the cooler to less than -20°C (e.g., less than -30°C, less than -40°C, less than -50°C, less than -60°C). In some embodiments, the lyophilization provided herein includes cooling the temperature of the cooler to greater than -90°C (e.g., greater than -80°C, greater than -70°C, greater than -60°C, greater than -50°C). In some embodiments, the lyophilization includes cooling to about -20°C to about -90°C. In some embodiments, the lyophilization provided herein includes cooling the temperature of the cooler to about -54°C.

[0156] In some embodiments, the lyophilization provided herein includes a pressure in the lyophilizer of at least 0.0001 mbar (e.g., at least 0.001 mbar, at least 0.01 mbar). In some embodiments, the lyophilization provided herein includes a pressure in the lyophilizer of at most 0.1 mbar (e.g., at most 0.01 mbar, at most 0.001 mbar). In some embodiments, the lyophilization provided herein includes a pressure in the lyophilizer of about 0.0001 mbar to about 0.1 mbar. In some embodiments, the lyophilization provided herein includes a pressure in the lyophilizer of about 0.01 mbar.

[0157] In some embodiments, the lyophilization provided herein is completed in at least 12 hours (e.g., at least 16 hours, at least 24 hours, at least 36 hours, at least 48 hours). In some embodiments, the lyophilization provided herein is completed in at most 72 hours (e.g., at most 48 hours, at most 36 hours, at most 24 hours). In some embodiments, the lyophilization provided herein is completed in about 12 hours to about 72 hours. In some embodiments, the lyophilization provided herein is completed in 24 hours.

[0158] In some embodiments, the mass of the lyophilization solution is at least 0.1 g (e.g., at least 1 g, at least 2 g, at least 4 g, at least 6 g, at least 8 g). In some embodiments, the mass of the lyophilization solution is at most 10 g (e.g., at most 8 g, at most 6 g, at most 4 g, at most 2 g, at most 1 g). In some embodiments, the mass of the lyophilization solution is from about 0.1 g to about 10 g. In some embodiments, the mass of the lyophilization solution is about 5.81 g, 8.29 g, 7.11 g, 4.06 g, 6.22 g, or 1.45 g.

[0159] In some embodiments, the mass of the product provided by lyophilization herein is at least 5 mg (e.g., at least 10 mg, at least 30 mg, at least 50 mg, at least 70 mg). In some embodiments, the mass of the product provided by lyophilization herein is at most 100 mg (e.g., at most 90 mg, at most 80 mg, at most 70 mg, at most 60 mg, at most 50 mg). In some embodiments, the mass of the product provided by lyophilization herein is from about 5 mg to about 100 mg. In some embodiments, the mass of the product provided by lyophilization is 57.9 mg, 83.1 mg, 70.8 mg, 71.0 mg, 40.7 mg, 61.9 mg, or 14.4 mg.

[0160] In some embodiments, the lyophilization provided herein results in amorphous (e.g., a-polymorphic) silybin, as described in Example 3 and FIG. 1. In some examples, the identity of the lyophilized material (e.g., amorphous (e.g., a-polymorphic) silybin) can be verified by proton NMR, as described in Example 3 and FIG. 2.

[0161] In some embodiments, the methods provided herein (e.g., generating) include spray drying. In some embodiments, concentrating includes spray drying. In some embodiments, spray drying is performed in the absence of a carrier material. In some embodiments, spray drying is performed in the absence of a polymer. In some embodiments, the absence of a carrier includes spray drying amorphous (e.g., a-polymorphic) silybin without a carrier (e.g., a polymer). In some embodiments, the absence of a polymer includes spray drying amorphous (e.g., a-polymorphic) silybin with less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a carrier (e.g., a polymer). In some embodiments, spray drying is performed in the presence of one or more sugars such as those described elsewhere herein. In some embodiments, the sugar includes mannitol and / or trehalose. In some embodiments, the sugar includes mannitol. In some embodiments, the sugar includes trehalose. In some embodiments, spray drying is performed in the presence of silicon dioxide. In some embodiments, silicon dioxide or sugar aids in the handling of the product such as the flowability of the composition. In some embodiments, when spray drying is performed in the presence of sugar, the silybin to sugar ratio is from about 90:10 to about 10:90 as described in Example 3. In some embodiments, the silybin to sugar ratio is 50:50. In some embodiments, the silybin to sugar ratio is 25:75. In some embodiments, the silybin to sugar ratio is 75:25.

[0162] In some embodiments, the spray drying provided herein is completed in at least 20 minutes (e.g., at least 30 minutes, at least 40 minutes, at least 50 minutes). In some embodiments, the spray drying provided herein is completed in a maximum of 60 minutes (e.g., a maximum of 50 minutes, a maximum of 40 minutes, a maximum of 30 minutes). In some embodiments, the spray drying provided herein is completed in about 20 minutes to about 60 minutes.

[0163] In some embodiments, in the spray drying provided herein, the temperature of the drying gas at the inlet to the drying chamber is at least 90°C (e.g., at least 95°C, at least 100°C, at least 105°C, at least 110°C). In some embodiments, in the spray drying provided herein, the temperature of the drying gas at the inlet to the drying chamber is at most 140°C (e.g., at most 130°C, at most 125°C, at most 120°C, at most 115°C, at most 110°C). In some embodiments, in the spray drying provided herein, the temperature of the drying gas at the inlet to the drying chamber is from about 90°C to about 140°C. In some embodiments, in the spray drying provided herein, the temperature of the drying gas at the inlet to the drying chamber is about 110°C. In the spray drying provided herein, the temperature of the drying gas at the inlet to the drying chamber is about 120°C.

[0164] In some embodiments, in the spray drying provided herein, the frequency of the piezoelectric film (e.g., spray %) is at least 40% (e.g., at least 45%, at least 50%, at least 55%, at least 60%). In some embodiments, in the spray drying provided herein, the frequency of the piezoelectric film (e.g., spray %) is at most 80% (e.g., at most 75%, at most 65%, at most 60%). In some embodiments, in the spray drying provided herein, the frequency of the piezoelectric film (e.g., spray %) is from about 40% to about 80%. In some embodiments, in the spray drying provided herein, the frequency of the piezoelectric film (e.g., spray %) is about 60%.

[0165] In some embodiments, in the spray drying provided herein, the rotation direction of the pump is clockwise at a normal speed (e.g., pump speed 1). In some embodiments, in the spray drying provided herein, the rotation of the pump is clockwise at twice the speed (e.g., pump speed 2).

[0166] In some embodiments, in the spray drying provided herein, the cooling temperature is at least 0 °C (e.g., at least 1 °C, at least 2 °C, at least 3 °C, at least 4 °C, at least 6 °C, at least 8 °C). In some embodiments, in the spray drying provided herein, the cooling temperature is at most 15 °C (e.g., at most 13 °C, at most 11 °C, at most 9 °C, at most 7 °C). In some embodiments, in the spray drying provided herein, the cooling temperature is from about 0 °C to about 15 °C. In some embodiments, the cooling temperature is about 6 °C, about 7 °C, or about 8 °C.

[0167] In some embodiments, in the spray drying provided herein, the mass of the solution to be spray dried is at least 10 g (e.g., at least 15 g, at least 20 g, at least 25 g, at least 30 g, at least 35 g). In some embodiments, in the spray drying provided herein, the mass of the solution to be spray dried is at most 50 g (e.g., at most 45 g, at most 40 g, at most 35 g, at most 30 g, at most 25 g, at most 20 g). In some embodiments, in the spray drying provided herein, the mass of the solution to be spray dried is from about 10 g to about 50 g. In some embodiments, the mass of the solution to be spray dried is about 31.97 g, about 30.20 g, about 31.60 g, about 31.05 g, about 35.02 g, about 32.35 g, or about 17.05 g.

[0168] In some embodiments, in the spray drying provided herein, the mass of the product is at least 0.005 g (e.g., at least 0.01 g, at least 0.05 g, at least 0.075 g, at least 0.1 g). In some embodiments, in the spray drying provided herein, the mass of the product is at most 0.2 g (e.g., at most 0.175 g, at most 0.15 g, at most 0.125 g, at most 0.1 g). In some embodiments, the mass of the product is from about 0.005 g to about 0.2 g. In some embodiments, the mass of the product is 0.13 g, 0.08 g, 0.14 g, 0.02 g, or 0.07 g.

[0169] In some embodiments, in any of the methods provided herein, generating comprises providing amorphous (e.g., a-polymorphic) silybin that is free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy) (e.g., the XRPD scan is free of reflections or peaks). In some embodiments, in any of the methods provided herein, generating comprises providing amorphous (e.g., a-polymorphic) silybin that is substantially free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy).

[0170] In some embodiments, a method for generating amorphous (e.g., a-polymorphic) silybin generates a silybin component (e.g., a silybin component that is free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC, SSNMR, or polarized microscopy)) (e.g., the XRPD scan is free of reflections or peaks). In some embodiments, a method for generating amorphous (e.g., a-polymorphic) silybin generates a silybin component (e.g., a silybin component that is substantially free of crystalline silybin (e.g., as determined by XRPD, melting point, DSC (e.g., modulated DSC), SSNMR, or polarized microscopy)).

[0171] In some embodiments, the methods provided herein provide a silybin (e.g., a silybin component, amorphous (e.g., a-polymorphic) silybin, or a-polymorphic silybin) composition having a chemical purity as determined by HPLC or reverse-phase HPLC and as described elsewhere herein. In some embodiments, the methods provided herein provide a silybin (e.g., a silybin component, amorphous silybin, or a-polymorphic silybin) composition having a physical purity as described elsewhere herein.

[0172] In some embodiments, the methods provided herein provide a silybin (e.g., a silybin component, amorphous silybin, or a-polymorphic silybin) composition having no single impurity exceeding 2% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.15%). In some embodiments, the methods provided herein provide an amorphous (e.g., a-polymorphic) silybin composition having no single impurity exceeding 2% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.15%).

[0173] Treatment method In some embodiments, provided herein are methods of administering any of the compositions provided herein (e.g., amorphous (e.g., a-polymorphic) silybin or a plurality of particles) to an individual (e.g., one in need thereof).

[0174] In some embodiments, the method includes administering a composition or a plurality of particles (e.g., any of the compositions and / or plurality of discrete particles disclosed herein) to an individual (e.g., a rodent, a monkey, a human, etc. (e.g., one in need thereof)). In some embodiments, the individual has a disorder or a symptom. In some embodiments, administering the composition (e.g., a therapeutically effective amount) treats or manages the disorder or symptom of the individual. The individual in need thereof may be suffering from the symptoms or signs of the disorder. Administration of the composition may help prevent or reduce the progression of the disorder, reduce or prevent the signs and / or symptoms of the disorder, and treat the disorder and / or its signs or symptoms. In some embodiments, the symptoms are physical, behavioral, emotional, mental, or a combination thereof.

[0175] In some embodiments, the disorders, behavioral states, neuropsychiatric states, mental states, and other such states and symptoms may be those specified in U.S. Patent Application Nos. 18 / 053,648, 18 / 102,268, and 18 / 102,296, which are hereby incorporated by reference in their entireties.

[0176] In some embodiments, the disorder is a symptom of a mental state, behavioral state, and / or neuropsychiatric state.

[0177] In some embodiments, the disorder is an attentional state (e.g., attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder), or a cognitive (e.g., neurocognitive) state. In some examples, the attentional state includes inattention, hyperactivity, impulsivity, challenging behavior, drug use, criminal behavior, or any combination thereof).

[0178] In some embodiments, the cognitive state is a cognitive (e.g., mild or severe) disorder. In some embodiments, the cognitive state (e.g., disorder) is dementia (e.g., Creutzfeldt-Jakob disease, frontotemporal, Huntington's disease, Parkinson's disease dementia, vascular dementia, or combinations thereof, regardless of the presence or absence of Lewy bodies). In some embodiments, the cognitive state (e.g., dysfunction) is Alzheimer's disease (e.g., early-onset, late-onset, familial Alzheimer's disease). In some embodiments, the cognitive state (e.g., dysfunction) is from brain injury (e.g., traumatic brain injury, stroke, aneurysm, tumor, encephalitis, hydrocephalus, hypoxic and anoxic injury, meningitis, and combinations thereof).

[0179] In some embodiments, the disorder is selected from the group consisting of schizophrenia, depression / suicide, anxiety, obsessive-compulsive disorder (OCD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), eating disorders such as anorexia nervosa, autism and autism spectrum disorder, Asperger's disease, neuropsychiatric diseases and disorders, sexual disorders such as erectile dysfunction, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, metabolic diseases such as obesity and diabetes, central nervous system disorders, peripheral nervous system disorders, Alzheimer's disease, snoring, sleep apnea (obstructive sleep apnea, central sleep apnea), insomnia, sleep disruption, restless legs syndrome, parasomnias, nightmares, night terrors, sleepwalking, hypersomnia (daytime sleepiness), narcolepsy, pain, and combinations thereof.

[0180] Additional examples of disorders, conditions, and symptoms that can be managed or treated include, by way of non-limiting example, apathy, fragile X syndrome, Down syndrome, migraine, cluster headache, mental disorders, neurodevelopmental disorders, attention deficit / hyperactivity disorder (ADHD), autism spectrum disorder, learning disorders, schizophrenia spectrum, psychotic disorders, bipolar disorder, depression, major depressive disorder (MDD), premenstrual dysphoric disorder (PMDD), suicidal ideation, mood-related disorders, panic disorder, panic attacks, phobias, agoraphobia, selective mutism, obsessive-compulsive disorder (OCD), hoarding disorder, trichotillomania (hair pulling disorder), skin picking disorder, substance / drug-induced obsessive-compulsive disorder, trauma-related disorders, traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), acute stress disorder, dissociative disorders, dissociative identity disorder, dissociative amnesia, anxiety, anxiety disorders, generalized anxiety disorder (GAD), social anxiety disorder, separation anxiety disorder, illness anxiety disorder, physical disabilities and diseases, somatic symptom disorder (somatization disorder), factitious disorder, nutritional supplementation disorders, eating disorders, anorexia, anorexia nervosa, bulimia nervosa, binge eating disorder, elimination disorders, enuresis, sleep disorders, insomnia, nightmare disorder, sleep apnea, central sleep apnea, narcolepsy, obstructive sleep apnea, hypopnea, and sleep-related hypoventilation, restless legs syndrome, jet lag, sexual dysfunction, premature ejaculation, erectile dysfunction, female orgasmic disorder, gender identity disorder, gender dysphoria, disruptivedisorder), impulse control disorder, behavioral disorder, disruptive behavior disorder, impulse control disorder, oppositional defiant disorder (ODD), aggression, kleptomania, pyromania, habit disorder, substance dependence, substance abuse, alcohol dependence, drug intoxication, opioid intoxication, cocaine intoxication, gambling dependence, tobacco dependence, food dependence, dependence on other forms of substances and behaviors, obesity, cognitive disorder, memory-related disorder, learning-related disorder, neurocognitive disorder, Alzheimer's disease, personality disorder, narcissistic personality disorder, Asperger syndrome, Tourette syndrome, Huntington's disease, Parkinson's disease, Lewy body disease, amyotrophic lateral sclerosis (ALS), Friedrich's ataxia, muscular dystrophy, prion disease, dementia, vascular dementia, dementia / neurocognitive problems caused by infectious diseases, dementia caused by drug abuse or toxin exposure, frontotemporal degeneration, mood disorder, delirium, aphasia, apraxia, agnosia, concussion, amnesia, anterograde amnesia, retrograde amnesia, body dysmorphic disorder, reactive attachment disorder, fragile X syndrome, Down syndrome, migraine, migraine headache, cluster headache, cardiovascular disease, inflammatory condition, fibromyalgia, pain, or a combination thereof.

[0181] In some embodiments, the disorder (e.g., a mental, behavioral, or neuropsychiatric condition) is a category of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In some embodiments, the disorder (e.g., a mental, behavioral, or neuropsychiatric condition) is a disorder in a non-DSM-5 category (e.g., ICD-10). In some embodiments, the disorder in the DSM-5 category is induced by stress. In some embodiments, the disorder in the non-DSM-5 category is induced by stress. In some embodiments, the disorder in the DSM-5 category is triggered by anxiety. In some embodiments, the disorder in the non-DSM-5 category is induced by anxiety. In some examples, the anxiety is GAD, OCD, panic disorder, PTSD, constructive impulsivity, phobia (e.g., social phobia (e.g., social anxiety disorder)), fear, or a combination thereof.

[0182] In some embodiments, administering a therapeutically effective amount of the composition comprises administering an amount of the composition that is below the threshold for adverse effects (e.g., an amount insufficient to cause an adverse effect). In some embodiments, the adverse effect is selected from the group consisting of nausea, vomiting, hallucinations, panic attacks, psychosis, muscle weakness, ataxia, or combinations thereof. In some examples, the adverse effect is a hallucination. A hallucination is a disruption in the sense of reality of an individual's perception, such as a change in perception, a change in body function, or a combination thereof.

[0183] In some embodiments, the method comprises administering a composition (e.g., a plurality of discrete particles) to an individual. In some embodiments, the administration is performed enterally (e.g., orally, rectally, etc.).

[0184] In some embodiments, administering the composition (e.g., a plurality of discrete particles) comprises co-administering an additional agent. In some embodiments, administering the composition (e.g., a plurality of discrete particles) comprises administering an additional agent before administering the composition. In some embodiments, administering the composition (e.g., a plurality of discrete particles) comprises administering an additional agent after administering the composition.

[0185] In some embodiments, the composition (e.g., an amorphous composition (e.g., comprising amorphous (e.g., a-polymorphic) silybin) is produced by any of the methods provided herein. Although the preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed in practicing the present invention. The following claims define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are intended to be encompassed thereby.

Examples

[0186] Example 1 Amorphous silybin is prepared by crash precipitation using MTBE. A saturated solution of silybin (180 mg in 0.9 mL) is prepared in trifluoroethanol, and an aliquot (0.45 mL) of this solution is directly filtered at ambient temperature through a 0.45 μm PTFE filter into a vial containing 4.5 mL of methyl tert-butyl ether (MTBE). The suspension is centrifuged (3000 rpm, 3 minutes), the solvent layer is removed, and the remaining solid is dried overnight under a nitrogen stream.

[0187] ASD preparation Prepare 1 kg of a 1% w / w PVP (polyvinylpyrrolidone) aqueous dispersion. While continuously mixing using a propeller mixer, 1 g of amorphous silybin solid is added to the aqueous dispersion. The dispersion is spray-dried to produce an amorphous solid dispersion.

[0188] Alternatively, a saturated solution of a silybin solution in a sufficient amount of trifluoroethanol is added to the aqueous PVP dispersion to achieve a 10% drug load of the drug. The mixture is spray-dried. The dispersion is spray-dried to produce an amorphous solid dispersion.

[0189] Example 2: Synthesis of amorphous (e.g., a-polymorphic) silybin using liquid-liquid extraction Synthesis of Compound 6 (3-[2-(dimethylamino)2-oxoacetyl]-1H-indol-4-yl acetate The synthetic scheme of compound 6 can be found in Scheme 1. A 2000 mL four-neck round-bottom flask was equipped with an overhead stirrer, a J-Kem temperature controller, a 250 mL dropping funnel, and a rubber septum through which a positive pressure of dry N2 was inserted. The septum was removed and the flask was sequentially charged with 1H-indol-4-ylacetate (5; 50.1 g, 285 mmol, 1 equiv) and anhydrous Et2O (700 mL). The flask was resealed with the septum and flushed with N2. The suspension was stirred for 10 minutes and then cooled to 0 °C in an ice-water bath for 30 minutes. The dropping funnel was charged with a solution of oxalyl chloride (37.1 mL, 428 mmol, 1.5 equiv) in Et2O (60 mL). The oxalyl chloride solution was added dropwise at a rate sufficient to keep the temperature below 5 °C in order to minimize the formation of dimers and other possible by-products. As the addition proceeded, a yellow slurry of 10 was formed and when the addition was complete, the mixture was stirred for 4 hours. Completion of the reaction was assayed by heating an aliquot of the reaction mixture in MeOH and checking by LCMS for the conversion of compound 10 to the corresponding methyl ester [3-(2-methoxy-2-oxoacetyl]-1H-indol-4-ylacetate]. Thereafter, heptane (400 mL) was added and the mixture was stirred at 0 °C for 30 minutes. The resulting yellow solid was rapidly filtered and washed successively with heptane (2 × 300 mL) and used rapidly in the next step. Rinsing the solid with heptane removes excess oxalyl chloride, thereby preventing the formation of tetramethyloxalylamide in the formation of 6. Tetramethyloxalylamide is a harmful impurity and is difficult to remove in the synthesis of 6. Compound 10 was rapidly dissolved in THF (500 mL) and cooled to 0 °C. A 2.0 M solution of dimethylamine in THF (175 mL) was added dropwise at a rate sufficient to maintain a temperature below 5 °C in order to minimize side reactions. After the addition was complete, pyridine (46 mL) in THF (100 mL) was added dropwise and the mixture was stirred well for 60 minutes. Heptane (600 mL) was added and the flask contents were suction filtered through a Buchner funnel. The filtered residue was transferred to a round-bottom flask, deionized H2O (1000 mL) was added, stirred for 30 minutes, and filtered through a Buchner funnel.The off-white solid was successively triturated in EtOAc (600 mL) and heptane (400 mL) for 40 minutes. The slurry was filtered through a Buchner funnel, and the solid was dried overnight in an oven at 40 °C to afford 6 as a pale yellow solid.

[0190] [Chemical formula]

[0191] Synthesis of Compound 7 Sirocin Procedure A: The synthesis of Compound 7 can be found in Scheme 2. A 2000 mL four-necked round-bottom flask was equipped with an overhead stirrer, a J-Kem temperature controller, a 250 mL dropping funnel, and a rubber septum through which a positive pressure of dry N2 was inserted. The septum was removed, and the flask was successively charged with 3-[2-(dimethylamino)-2-oxoacetyl]-1H-indol-4-yl acetate (6; 31.5 g, 115 mmol) and 2-CH3-THF (1000 mL). The flask was immersed in an ice bath at 0 °C, and a solution of 2.3 M LiAlH4 in 2-CH3-THF (140 mL, 322 mmol) was added through the 250 mL dropping funnel. The dropping funnel was rinsed with additional 2-CH3-THF (20 mL). The LiAlH4 solution was added dropwise at a rate that maintained the temperature below 20 °C. After the addition, the ice bath was removed, and the mixture was stirred for 30 minutes. Analytical HPLC showed a single major peak, which was found to be the intermediate compound 11 (hydroxy sirocin intermediate). The pale yellow solution was heated to reflux (80 °C) with a heating mantle and turned ivory after 3 hours. An accumulation of yellow solid was observed on the side of the round-bottom flask.

[0192] The reaction mixture was assayed by analytical HPLC, which showed >90% completion with respect to the product peak 7. The heating mantle was removed and the flask was cooled to 50 °C. The flask was cooled again to 20 °C. The reaction was quenched by the successive addition of 3 drops of aqueous 1 M NaOH and 3 drops of deionized H2O. The mixture was diluted with THF (500 mL) and stirred for 20 minutes. The mixture was filtered through a Buchner funnel and the filtrate was kept under N2. The filter cake was quickly slurried again with 200 mL of [10% solution of (7% ammonia in MeOH) in CH2Cl2] and THF (500 mL). The filtrates were then combined, concentrated, and a green solid was obtained. The solid was triturated with 1:1 EtOAc / heptane (50 mL) and then filtered through a Buchner funnel. The dark green solid was dried in an oven at 40 °C overnight to give dried silocin (7) as a dark green solid.

[0193]

Chem.

[0194] Synthesis of Compound 11 Hydroxysilocin The synthesis of Compound 11 can be found in Scheme 2. Intermediate 11 was isolated by performing essentially the same reaction sequence described for Compound 7 on a smaller scale, except that the intermediate 11 was stirred at room temperature for 4 hours instead of refluxing. After quenching, the filtrate was concentrated and the residue was purified by flash column chromatography (SiO2, 100:10:1 CH2Cl2 / CH3OH / NH4OH) to give 11 as a gray solid.

[0195] Procedure B: The reduction step was carried out using 6 (40.21 g, 135.2 mmol) and 2.3 M LiAlH4 in 2-CH3-THF (188.1 mL, 432.5 mmol) using essentially the same protocol as described in Procedure A. The reaction was quenched by dropwise addition of THF / H2O (27:100, 50 mL) at a rate that maintained the temperature below 30 °C. Anhydrous Na2SO4 (100 g), followed by silica gel (50 g) and DCM (400 mL) were added. The mixture was stirred for 10 minutes and filtered through a Buchner funnel. The filter cake was washed with a DCM / CH3OH mixture (9:1, 1500 mL). The filtrates were then combined and concentrated to afford a pale green solid. The solid was triturated with 1:1 EtOAc / heptane (50 mL) and then filtered through a Buchner funnel. The off-white solid was dried in an oven at 40 °C overnight to give dried silosine (7) as an off-white solid.

[0196] Synthesis of Benzyl {3-[2-(benzyldimethylammonio)ethyl]-1H-indol-4-yl} phosphate of Compound 9 The synthesis of compound 9 can be found in Scheme 3. A 2000 mL four-neck round-bottom flask was equipped with an overhead stirrer, a J-Kem temperature controller, a 100 mL dropping funnel, and a rubber septum through which a positive pressure of dry N2 was inserted. The septum was removed, and the flask was sequentially charged with shirosine (7; 10.3 g, 60.2 mmol) and anhydrous THF (500 mL). The mixture was stirred for 15 minutes, and the flask was immersed in a solid CO2 / acetone cooling bath at -78 °C. When the internal temperature of the reaction reached -67 °C, a solution of 2.5 M BuLi in hexane (28.9 mL, 72.3 mmol) was added dropwise over several minutes while maintaining the internal temperature below -60 °C. The olive green reaction mixture was stirred for 10 minutes, then tetrabenzyl pyrophosphate (35.7 g, 66.2 mmol) was added all at once, and the mixture was stirred well. After 1.5 hours, the solid CO2 / acetone cooling bath was removed, and the temperature was slowly raised to -25 °C over 2 hours, at which point LCMS indicated completion of the reaction to compound 15 with no trace of compound 10 in the reaction mixture. Amino-bonded silica gel (30 g) was added all at once, and the reaction was diluted with EtOAc (600 mL). The dark-colored mixture was filtered through a pad of celite and washed with EtOAc (400 mL). The filter cake was slurried again with EtOAc (400 mL) for 10 minutes and filtered again. The combined filtrates were concentrated and transferred to a 500 mL single-neck round-bottom flask. The gray oil was redissolved in DCM (100 mL) and boiled with a heat gun for 5 minutes. The flask was allowed to reach room temperature and then held at 4 °C overnight. The crude gray zwitterionic precipitate 9 was filtered through a Buchner funnel and then triturated with DCM (4 x 100 mL). The zwitterionic precipitate 9 was transferred to a 250 mL single-neck round-bottom flask and dried completely in a vacuum oven at 40 °C overnight to afford a pale purple solid.

[0197] [Chemical formula]

[0198] Synthesis of amorphous (e.g., a-polymorph) shirosine by liquid-liquid extraction The synthesis of compound 1, silibinin, can be found in Scheme 4. Once the synthesis of intermediate 9 was completed, the synthesis of amorphous (α-polymorphic) silibinin 1 was achieved through the following steps. To a 2000 mL round-bottom flask, 9 (16.9 g, 35.6 mmol) was added, followed by CH3OH (1200 mL). The mixture was degassed and refilled with N2. 10% Pd / C (1.1 g) was added, the mixture was degassed, and a 1 atm H2 balloon was refilled. The reaction mixture was stirred at room temperature overnight. LCMS indicated the completion of the reaction and no starting material remained (subsequent reactions revealed that hydrogenolysis was complete after 30 minutes). The flask was degassed and refilled with N2, and the suspension was filtered through a pad of celite via a Buchner funnel. The filter pad was washed with CH3OH (500 mL). 150 mL of the reaction solution was diluted with 450 mL of H2O, the pH was adjusted to pH 9 with NH3 (aqueous solution, 25%), and the mixture was extracted twice with 350 mL of DCM at room temperature (room temperature = 21.5 °C ± 2 °C). The aqueous phase was reduced in volume under reduced pressure (depletion of CH3OH and NH3) to produce an aqueous solution of amorphous silibinin 1.

[0199] Purity: The purity was determined to be 98.3% as confirmed by reverse-phase-HPLC (Agilent 1220 Infinity) at 267 nm.

[0200]

Chemical Structure

[0201] Example 3: Freeze-drying, spray-drying of amorphous silibinin, and stability testing Freeze-drying (sugar-free), XRPD, and NMR analysis 50 mL of the aqueous solution from Example 2 (amorphous silibinin 1) was freeze-dried using a Christ Alpha1-2 freeze dryer. The solution was transferred to a round-bottom flask (100 mL, NS29). The solution was filtered through a 0.2 μm PTFE syringe filter and freeze-dried at room temperature for 24 hours. The yield was 55 mg. Freeze-drying yielded a fine, colorless powder.

[0202] Polarized microscopy: Before XRPD analysis, the freeze-dried powder was analyzed using polarized microscopy. Before filling into a borosilicate capillary for XRPD analysis, it was confirmed that the sample did not contain a crystalline structure. The apparatus used was a Leitz (Wetzlar, Germany) Ortholux (model I) equipped with a polarization cooler “Achr.0.90P” (Leitz Wetzlar Germany).

[0203] XRPD methodology: The freeze-dried powder was filled into a borosilicate capillary (diameter: 0.7 mm) and sealed. Subsequently, the powder diffraction pattern was recorded in a transmission Debye-Scherrer configuration (device: STOE StadiP). Using a copper source, Cu Kα1-radiation was generated (λ = 1.540598 Å). Overview measurements were recorded in the range of 2θ from 2 to 40° with a step width of 0.015° and a collection time of 5 seconds or 30 seconds per step. A single-photon counting strip detector (DECTRIS MYTHEN 1K) was used to detect the diffracted X-ray beam, and WinXPOW software (STOE) was used for qualitative evaluation of the diffractogram.

[0204] Figure 1 shows the XRPD of freeze-dried silybin, which does not show sharp reflections equal to the crystalline version of silybin used as a reference spectrum, indicating an amorphous (e.g., a-polymorphism) phase.

[0205] Proton NMR of the freeze-dried product in methanol-D4 was performed. The NMR was compared with the reference. Proton NMR confirmed the structure of the freeze-dried silybin (Figure 2).

[0206] Spray drying of silybin Seven silybin-containing solutions were prepared and spray-dried. 1. Silybin in H2O: Trehalose (50:50) 1% → Sample ID HSR2305_01 2. Silybin in H2O: Trehalose (25:75) 1% → Sample ID HSR2305_02 3. Sirobin in H2O: Mannitol (25:75) 1% → Sample ID HSR2305_03 4. Sirobin in H2O: Trehalose (75:25) 1% → Sample ID HSR2305_04 5. Sirobin in H2O: Mannitol (75:25) 1% → Sample ID HSR2305_05 6. Sirobin in H2O: Mannitol (50:50) 1% → Sample ID HSR2305_06 7. Sirobin in H2O (100) 1% → Sample ID HSR2305_07

[0207] The solutions were transferred to round-bottom flasks for the experiment. Solutions 1 - 3 were completely dissolved, while solutions 4 - 7 contained undissolved material. Therefore, they were continuously stirred at room temperature during the experiment to ensure a uniform product distribution using a compact stirrer IKA Ministars 20 Control equipped with a radial PTFE stirrer (BOLA stirring shaft (article number: C382 - 02)).

[0208] All solutions were dried using a nanospray dryer (Buchi, B - 90). Regarding the properties of the products, it was found that an increase in the trehalose content led to an improvement in the fluidity of the powder.

[0209] An increase in the mannitol content resulted in a strong adhesion of the dried material to the vapor deposition electrode, which may lead to a decrease in the yield of the solution containing mannitol.

[0210] For all experiments, a stainless - steel spray membrane with a mesh size of 7μm was used. Drying was carried out in a closed circuit under a nitrogen atmosphere (3% O2) with a drying gas volume flow rate of 130 L / min.

[0211] The process parameters of the spray - drying experiment can be found in Table 1.

[0212]

Table 1

[0213] In Table 1, T in [°C] is the temperature of the drying gas at the inlet to the drying chamber. Spray [%] corresponds to the frequency of the piezoelectric film (excited to vibrate by ultrasonic waves at 60 kHz). Pump setting: 1 - clockwise pump rotation direction at normal speed, 2 - clockwise pump rotation at twice the speed. T cooling is the temperature of the dehumidifier.

[0214] After the analysis of sample HSR2305_03, the drying temperature increased slightly, and due to the strong adhesion of the product, incomplete drying was initially suspected. Since the product of HSR2305_05 adhered strongly to the electrode again, the behavior of this product is rather suspected to be due to a high mannitol content.

[0215] The mass of the product was measured on a scale accurate to 50 mg. The mass of the product of HSR2305_05 was not determined.

[0216] The solution volume of HSR2305_07 was only 20 mL, so less volume was sprayed compared to the 40 mL supply solution available in each of the other tests.

[0217] The test durations of the various experiments varied due to changes in pump settings and slight clogging in the estimated spray film, which may have caused non-uniformity of the spray flow. Generally, all drying tests were carried out without problems.

[0218] Samples stored at room temperature for 2 - 4 weeks are analyzed by XRPD according to the following methodology: The spray - dried samples are filled into borosilicate capillaries (diameter: 0.7 mm) and sealed. Subsequently, the powder diffraction pattern is recorded in a transmission Debye - Scherrer configuration (device: STOE StadiP). A copper source is used to generate Cu kα1 - radiation (λ = 1.540598 Å). Overview measurements are recorded in the range of 2θ from 2 to 40° with a step width of 0.015° and a collection time of 5 seconds per step. A single - photon - counting strip detector (DECTRIS MYTHEN 1K) is used to detect the diffracted X - ray beam, and WinXPOW software (STOE) is used for qualitative evaluation of the diffractogram.

[0219] Lyophilization with sugar Seven silybins containing aqueous solution (prepared beforehand for spray - drying experiments) were lyophilized in a Christ Alpha1 - 2 lyophilizer. 1. Silybin in H2O: Trehalose (50:50) 1% → Sample ID FSC2304_01_02 2. Silybin in H2O: Trehalose (25:75) 1% → Sample ID FSC2304_01_03 3. Silybin in H2O: Mannitol (25:75) 1% → Sample ID FSC2304_01_04 4. Silybin in H2O: Trehalose (75:25) 1% → Sample ID FSC2304_01_05 5. Silybin in H2O: Mannitol (75:25) 1% → Sample ID FSC2304_01_06 6. Silybin in H2O: Mannitol (50:50) 1% → Sample ID FSC2304_01_07 7. Silybin in H2O (100) 1% → Sample ID FSC2304_01_08

[0220] For the experiment, the solution was transferred to a round-bottom flask (100 mL, NS29). Solutions 4, 5, and 7 were gently heated to 40 °C to dissolve the precipitated solid. All solutions were filtered through a 0.2 μm PTFE syringe filter and freeze-dried at room temperature for 24 hours. All samples were weighed after the completion of freeze-drying. The results can be found below. As expected, there was no significant loss of substance. The process parameters of the test are listed in Table 2.

[0221]

Table 2

[0222] In Table 2, T st [°C] is the temperature of the solution at the start of freeze-drying, r.t. is the room temperature of 21 + / - 2 °C, T cooling [°C] is the temperature of the cooler, and P [mbar] is the pressure inside the freeze-dryer.

[0223] Samples stored at room temperature for 2 - 4 weeks were analyzed by XRPD according to the following methodology: The freeze-dried sample was filled into a borosilicate capillary (diameter: 0.7 mm) and sealed. Subsequently, the powder diffraction pattern was recorded in a transmission Debye-Scherrer configuration (device: STOE StadiP). A copper source was used to generate Cu Kα1-radiation (λ = 1.540598 Å). Overview measurements were recorded in the range of 2 - 40° of 2θ with a step width of 0.015° and a collection time of 5 seconds per step. A single-photon counting strip detector (DECTRIS MYTHEN 1K) was used to detect the diffracted X-ray beam, and the WinXPOW software (STOE) was used for the qualitative evaluation of the diffractogram.

[0224] Stability study Samples from the lyophilization experiment (sugar-free) were stored at room temperature (RT = 25 °C) for one week. On the first day, the samples were subjected to polarized light microscopy (as described above). The samples were confirmed to contain no crystal structure. The samples tested after one week of storage were identified as the long scan sample of silybin lyophilizate (PSI LYO LT) and the short scan sample of silybin lyophilizate (PSI LYO ST). PSI LYO ST and PSI LYO LT were analyzed by XRPD according to the following methodology. The lyophilized powder was filled into a borosilicate capillary (diameter: 0.7 mm) and sealed. Subsequently, the powder diffraction pattern was recorded in a transmission Debye-Scherrer configuration (device: STOE StadiP). A copper source was used to generate Cu kα1-radiation (λ = 1.540598 Å). In the range of 2θ from 2 to 40°, overview measurements were recorded with a step width of 0.015° and a collection time of 30 seconds per step (PSI LYO LT) or 5 seconds per step (PSI LYO ST). A single photon counting strip detector (DECTRIS MYTHEN 1K) was used to detect the diffracted X-ray beam, and the WinXPOW software (STOE) was used for the qualitative evaluation of the diffractogram.

[0225] Figure 3 shows that there are no sharp reflections in either the short scan sample of silybin lyophilizate (PSI LYO ST) or the long scan sample of silybin lyophilizate (PSI LYO LT). Therefore, after one week of storage at room temperature, the absence of sharp reflections indicated that the long and short scan samples of silybin lyophilizate maintained a surprisingly amorphous / crystalline phase (in the absence of sugar or polymer). The results of the measurement indicated the absence of long-range order (i.e., crystallinity) in the silybin lyophilizate sample.

[0226] Dissolution assay A saturated solution of psilocybin is produced in pure water (ReOS, degassed with N2 (excluding air (CO2), N2 quality 5.0)). The conductivity of the solution is measured as a reference for fully dissolved data points. The method is repeated with a new sample in a dry container by adding substances while stirring, adding water, and inserting electrodes. The time when the conductivity of the solution increases and reaches 90% of the initial measurement value is (t90). A Schott Instruments LAB 960 conductivity meter (range of 500 mS / cm to 0.001 μS / cm) can be used (see http: / / en.gihonjumasentosa.com / product / schott-lab-960-conductivity-bench-laoratory-meter-p718127.aspx, the content of which is incorporated herein by reference).

Claims

1. A method for producing an amorphous composition containing psilocybin, i. Synthesizing the components of psilocybin, ii. A method comprising producing an amorphous composition containing the psilocybin components.

2. The method according to claim 1, wherein the production includes spray drying, wet granulation / fluidized bed drying, wet granulation / microwave drying, wet granulation / tray drying, freeze-drying, drum drying, precipitation, hot melt extrusion, supercritical fluidization, or pulse combustion drying.

3. The method according to claim 1, wherein the production includes spray drying.

4. The method according to claim 1, wherein the production includes freeze-drying.

5. The method according to any one of claims 2 to 4, wherein the freeze-drying or spray-drying is carried out in the absence of a carrier.

6. The method according to claim 1, wherein the psilocybin component is the sole component of the amorphous composition.

7. The method according to claim 2, wherein the production is carried out by freeze-drying or spray-drying in the presence of one or more sugars.

8. The method according to claim 7, wherein the one or more sugars include mannitol and / or trehalose.

9. The method according to claim 3, wherein the spray drying is performed in the presence of silicon dioxide.

10. The method according to claim 1, wherein the amorphous composition is completely free of crystalline psilocybin.

11. The method according to claim 1, wherein the psilocybin component does not contain crystalline psilocybin at all.

12. The method according to claim 1, wherein the synthesis provides α-polymorphic psilocybin that does not contain crystalline psilocybin at all, and the synthesis step does not involve crystallization of psilocybin.

13. The method according to claim 1, wherein the resulting product is α-polymorphic psilocybin, which is determined to be completely free of crystalline psilocybin by XRPD, melting point, DSC, SSNNMR, or polarized light microscopy.

14. The method according to claim 1, wherein the synthesis provides a psilocybin component that does not contain more than 2% of a single impurity and is determined to have a chemical purity of at least 95% by high-performance liquid chromatography (HPLC) or reversed-phase HPLC.

15. The method according to claim 1, wherein the product is determined to contain no single impurity exceeding 2%, and to have a chemical purity of at least 95% by high-performance liquid chromatography (HPLC) or reversed-phase HPLC.

16. The method according to claim 1, wherein at least 25% by weight of the amorphous composition is α-polymorphic psilocybin.

17. The method according to claim 1, wherein the psilocybin component comprises amorphous psilocybin.

18. The method according to claim 1, wherein the amorphous composition is not a dispersion.

19. A synthetic α-polymorphic psilocybin that is completely free of crystalline psilocybin.

20. The synthetic a-polymorphic psilocybin according to claim 19, wherein the synthetic a-polymorphic psilocybin has a chemical purity of at least 95% and does not contain more than 2% of any single impurity.

21. The synthetic a-polymorphic psilocybin according to claim 20, wherein the synthetic a-polymorphic psilocybin has a chemical purity of at least 98%.

22. The synthetic a-polymorphic psilocybin according to claim 19, wherein the synthetic a-polymorphic psilocybin is concentrated.

23. The synthetic a-polymorphic psilocybin according to claim 22, wherein the concentrated synthetic a-polymorphic psilocybin is spray-dried a-polymorphic psilocybin.

24. The synthetic α-polymorphic psilocybin according to claim 22, wherein the concentrated synthetic α-polymorphic psilocybin composition is freeze-dried α-polymorphic psilocybin.

25. A synthetic α-polymorphic psilocybin composition comprising the synthetic α-polymorphic psilocybin described in claim 19.

26. The synthetic α-polymorphic psilocybin composition according to claim 25, further comprising one or more sugars.

27. The synthetic α-polymorphic psilocybin composition according to claim 25, further comprising silicon dioxide.

28. The synthetic a-polymorphic psilocybin composition according to claim 25, wherein the a-polymorphic psilocybin composition does not contain a carrier.

29. The synthetic a-polymorphic psilocybin composition according to claim 25, wherein the a-polymorphic psilocybin composition is not a dispersion.

30. A synthetic α-polymorphic psilocybin composition, wherein the α-polymorphic psilocybin composition is free of a carrier and completely free of crystalline psilocybin after being stored at a controlled room temperature for at least one week.

31. A method for producing synthetic α-polymorphic psilocybin, a. To provide protected psilocybin, b. To provide psilocybin by deprotecting the protected psilocybin in a reaction solvent, c. Extracting the psilocybin from the reaction solvent into an aqueous medium, and washing the aqueous medium with an organic solvent, d. Concentrating the aqueous medium containing psilocybin, e. A method comprising collecting amorphous psilocybin.

32. A method for preparing a synthetic α-polymorphic psilocybin composition, a. To provide protected psilocybin, b. To provide psilocybin by deprotecting the protected psilocybin in a reaction solvent, c. Extracting the psilocybin from the reaction solvent into an aqueous medium, and washing the aqueous medium with an organic solvent, d. Concentrating the aqueous medium containing psilocybin, e. A method comprising collecting amorphous psilocybin.

33. The method according to claim 32, wherein at least 50% of the composition is composed of amorphous psilocybin.

34. The protected psilocybin is represented by the following structure: 【Chemistry 1】 During the ceremony, The method according to claim 32, wherein each R is independently a hydrogen atom or a protecting group.

35. The method according to claim 34, wherein both R are protecting groups.

36. The method according to claim 34, wherein the protecting group includes benzene.

37. The method according to claim 34, wherein both Rs are hydrogen.

38. The method according to claim 35, wherein the protecting group is methylbenzene.

39. The method according to claim 32, wherein deprotection includes hydrocracking.

40. The method according to claim 32, wherein the reaction solvent includes an alcohol.

41. The method according to claim 32, wherein the reaction solvent comprises methanol.

42. The method according to claim 32, wherein the organic solvent contains a halocarbon.

43. The method according to claim 32, wherein the organic solvent includes dichloromethane.

44. The method according to claim 32, wherein the aqueous medium has a pH of 9.

45. The method according to claim 32, wherein the concentration includes spray drying.

46. The method according to claim 32, wherein concentration includes freeze-drying.

47. The method according to claim 32, wherein the method does not require distillation of the aqueous medium.

48. The method according to claim 32, wherein the synthetic a-polymorphic psilocybin composition or the synthetic a-polymorphic psilocybin is at least 98% pure without requiring crystallization.

49. A composition in which at least 50% of the composition is composed of amorphous psilocybin.

50. The composition according to claim 49, wherein at least 60% of the composition is composed of amorphous psilocybin.

51. The composition according to claim 49, wherein the amorphous psilocybin is at least 10% amorphous.

52. The composition according to claim 49, wherein the amorphous psilocybin is present in the composition with a purity of at least 85%.

53. The composition according to claim 49, wherein the composition comprises less than 20% of the polymer.

54. The composition according to claim 49, wherein the amorphous psilocybin is not dispersed throughout the polymer matrix.

55. The composition according to claim 49, wherein the composition is stable for at least one week.

56. The composition according to claim 49, wherein the psilocybin has never been crystalline.

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