Solid forms of berberine ursodeoxycholic acid and compositions and methods thereof

Abstract

To provide novel solid forms (e.g., crystalline forms) of berberine ursodeoxycholate (BBR-UDCA) having one or more desirable properties, such as high stability, high crystallinity, high purity, low hygroscopicity, favorable dissolution properties and / or favorable mechanical properties.SOLUTION: There is provided a solid form, which is Form A of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values selected from the group consisting of specific values obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] <Priority claims and related applications> This application claims the benefit of priority to Chinese Application No. 201710335467.5, filed on May 12, 2017, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention generally relates to a solid form of berberine ursodeoxycholic acid, as well as its pharmaceutical composition, its preparation method, and its therapeutic use.In particular, the present invention relates to a solid form (e.g., crystalline or amorphous form) of berberine ursodeoxycholic acid and its pharmaceutical composition, which are useful in treating and / or preventing various diseases or disorders, including metabolic disorders, heart disease, neurodegenerative diseases, and liver diseases. [Background technology]

[0003] [ka] The compound berberine-ursodeoxycholic acid (BBR-UDCA), represented by the formula: is disclosed in International Publication No. 2016 / 015634A1 (PCT / CN2015 / 085350, filed July 28, 2015, priority date July 29, 2014), the contents of which are incorporated herein by reference in their entirety. The preparation of this compound was disclosed therein, as were certain beneficial biological activities of this compound.

[0004] Solid forms are of particular interest in the development of suitable dosage forms of pharmaceuticals. Because impurities present can cause undesirable toxic effects, it is desirable to have a process for producing a compound with a selected solid form in high purity when the compound is used in clinical studies or commercial products. If the solid form is not kept constant during clinical trials or stability testing, the exact dosage form used or tested may not be comparable from lot to lot.

[0005] Certain solid forms may also exhibit improved thermodynamic stability or be more easily manufactured in large quantities with high purity, making them more suitable for inclusion in pharmaceutical formulations. Different solid forms of active pharmaceutical ingredients can result in changes in the drug's solubility, dissolution rate, pharmacokinetics, and ultimately its bioavailability and efficacy in patients. Certain solid forms may exhibit other advantageous physical properties, such as a lack of hygroscopic tendency, improved filterability, solubility, and improved dissolution rate due to different lattice energies.

[0006] Therefore, finding which solid form is most stable under each condition of interest and under processes that result in changes in solid form is critical to the design of drug manufacturing processes to ensure that the final product is in the desired solid form. There remains a continuing need to identify new solid forms with desirable physicochemical properties suitable for preparation and therapeutic use. Summary of the Invention

[0007] The present invention provides novel solid forms (e.g., crystalline forms) of BBR-UDCA that have one or more desirable properties, such as high stability, high crystallinity, high purity, low hygroscopicity, favorable dissolution characteristics, and / or favorable mechanical properties, etc. In particular, the solid forms of BBR-UDCA disclosed herein offer improved physical stability and / or physicochemical properties suitable for clinical research, product manufacturing, and therapeutic applications.

[0008] The solid forms disclosed herein can be utilized to treat a variety of diseases or disorders, such as diabetes, diabetic complications, dyslipidemia, dyslipidemia in statin-intolerant patients, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, diabetic dyslipidemia, obesity, metabolic syndrome, prediabetes, heart disease, neurodegenerative disease, sarcopenia, muscle atrophy, inflammation, and cancer, as well as a variety of liver diseases or disorders, such as fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cholestatic liver disease, or hepatic graft-versus-host disease. The compounds of the present invention are also useful for improving liver function in chronic viral- and alcohol-related liver disease.

[0009] In one aspect, the present invention relates generally to a solid form of BBR-UDCA Form A, which has the following peaks: 3.98, 7.06, 7.34, 7.93, 8.79, 9.47, 11.70, 11.94, 12.34, 12.55, 13.90, 14.17, 15.14, 15.50, 16.16, 16.54, 16.78, 17.53, 17.06, 17.26, 17.66, 17.08, 17.29, 17.34, 17.93, 18.79, 18.47, 18.80, 18.66, 18.84, 18.68, 18.86, 18.88, 18.90, 19.17, 20.14, 20.14, 20.26, 20.30, 20.40, 20.50, 20.66, 20.70, 20.86, 20.90, 21.14, 21.26, 21.50, 21.16, 21.50, 21.66, 21.70, 21.86, 21.90, 22.14, 22.26, 22.50, 22.70, 22.86, 22.90, 23.17, 23.14 ... and 30.49° (±0.2°).

[0010] In another aspect, the invention generally relates to a solid form, Form B of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 7.39, 9.31, 12.41, 13.14, 14.37, 14.76, 15.53, 18.65, 21.79, 22.87, 25.27, 25.53, and 28.12° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0011] In yet another aspect, the invention generally relates to a solid form, Form C, of ​​BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 7.23, 10.42, 12.10, 13.37, 14.24, 14.48, 15.28, 15.95, 17.00, 18.17, 20.12, 21.77, and 25.47° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0012] In yet another aspect, the invention generally relates to a solid form that is Form D of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 4.24, 6.79, 8.50, 10.25, 11.50, 13.62, 14.74, 15.20, 17.92, 18.39, 22.91, and 25.73° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0013] In yet another aspect, the present invention relates generally to a solid form of BBR-UDCA, Form E, which has the following spectral signatures: 8.59, 10.55, 11.36, 11.86, 12.46, 13.08, 13.38, 14.34, 15.57, 17.24, 17.72, 18.43, 19.66, 19.84, 20.35, 21.25, 22.00, 23.00, 24.00, 25.00, 26.00, 27.00, 28.00, 29.00, 30.00, 31.00, 32.00, 33.00, 34.00, 35.00, 36.00, 37.00, 38.00, 39.00, 40.00, 41.00, 42.00, 43.00, 44.00, 45.00, 46.00, 47.00, 48.00, 49.00, 50.00, 51.00, 52.00, 53.00, 54.00, 55.00, 56.00, 57.00, 58.00, 59.00, 60.00, 61.00, 62.00, 63.00, 64.00, 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, 72.00, 73.00, 74. 91, 21.36, 21.95, 23.21, 24.67, 25.04, 25.82, 26.12, 27.01, 27.84, 28.97, 30.35, 33.33, 34.54, and 36.06° (±0.2°).

[0014] In yet another aspect, the invention generally relates to a solid form, Form H, of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 13.05, 14.63, and 25.46° (±0.2°) obtained using Cu Kα radiation (λ=1.540598 Å, λ=1.544426 Å, intensity ratio λ / λ=0.50).

[0015] In yet another aspect, the invention generally relates to a solid form that is Form I of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 4.19, 7.64, 10.03, 13.32, 13.84, 14.83, 16.73, 22.73, 25.61, and 28.57° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0016] In yet another aspect, the present invention generally relates to a solid form of BBR-UDCA Form J, which is a Cu having an X-ray powder diffraction (XRPD) pattern obtained using Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50) and including one or more peaks at 2θ values ​​selected from the group consisting of 4.61, 6.32, 7.38, 8.22, 9.21, 10.57, 11.73, 12.13, 12.62, 12.96, 13.87, 14.55, 14.78, 15.81, 16.48, 17.69, 18.39, 19.01, 20.06, 21.25, 22.13, 23.20, 24.47, 24.89, 26.31, 27.98, 30.25, and 33.35° (±0.2°).

[0017] In yet another aspect, the invention generally relates to a solid form, Form P, of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 3.11, 5.01, 5.78, 7.26, 9.20, 10.10, 10.79, 11.65, 13.70, 14.59, 15.22, 16.19, 16.54, 17.05, 18.06, 18.68, 20.52, 21.09, 21.73, 22.49, 24.73, 25.42, 25.94, and 30.11° (±0.2°) obtained using Cu Kα radiation (λ=1.540598 Å, λ=1.544426 Å, intensity ratio λ / λ=0.50).

[0018] In yet another aspect, the invention generally relates to a solid form, Form W of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 6.49, 7.16, 8.51, 10.21, 12.01, 13.13, 13.90, 14.42, 15.18, 15.57, 16.03, 16.45, 16.74, 17.08, 17.85, 18.39, 19.61, 20.43, 21.39, 21.70, 23.51, and 25.21° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0019] In yet another aspect, the present invention generally relates to a solid form of BBR-UDCA Form X, which is a Cu having an X-ray powder diffraction (XRPD) pattern obtained using Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50) containing one or more peaks at 2θ values ​​selected from the group consisting of: 3.63, 6.61, 7.24, 10.49, 11.95, 13.51, 14.26, 14.54, 15.14, 16.01, 16.82, 18.28, 20.26, 21.08, 21.49, 21.90, 25.60, 26.40, 27.31, 29.34, 30.59, 31.01, 34.04, 34.68, 36.91° (±0.2°).

[0020] In yet another aspect, the invention generally relates to a hemi-nonehydrate solid form of BBR-UDCA.

[0021] In yet another aspect, the invention generally relates to compositions comprising one or more solid forms disclosed herein (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X).

[0022] In yet another aspect, the invention generally relates to compositions comprising two or more solid forms disclosed herein (e.g., two or more of Forms A, B, C, D, E, H, I, J, P, W, and X).

[0023] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form A of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0024] In yet another aspect, the invention generally relates to pharmaceutical compositions comprising Form B of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0025] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form C of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0026] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form D of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0027] In yet another aspect, the invention generally relates to pharmaceutical compositions comprising Form E of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0028] In yet another aspect, the invention generally relates to pharmaceutical compositions comprising BBR-UDCA Form H and a pharmaceutically acceptable excipient, carrier, or diluent.

[0029] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form I of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0030] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising BBR-UDCA Form J and a pharmaceutically acceptable excipient, carrier, or diluent.

[0031] In yet another aspect, the invention generally relates to pharmaceutical compositions comprising BBR-UDCA Form P and a pharmaceutically acceptable excipient, carrier, or diluent.

[0032] In yet another aspect, the invention generally relates to pharmaceutical compositions comprising BBR-UDCA Form W and a pharmaceutically acceptable excipient, carrier, or diluent.

[0033] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form X of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0034] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0035] In yet another aspect, the present invention generally relates to a method of treating, alleviating, or preventing a metabolic disorder, cardiac disease, neurodegenerative disease, or liver disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0036] In yet another aspect, the present invention generally relates to methods of treating, alleviating, or preventing a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as disclosed herein, or a unit dosage form as disclosed herein, that is effective to treat, prevent, or alleviate one or more diseases or disorders selected from fatty liver, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), cholestatic liver disease, hepatic graft-versus-host disease, primary sclerosing cholangitis, chronic virus-related liver disease, alcohol-related liver disease, metabolic diseases or disorders such as prediabetes, diabetes, hyperlipidemia, hypercholesterolemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, obesity, or related diseases or disorders in a mammal, including a human.

[0037] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form A. The method includes the steps of forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with an organic solvent and a co-solvent of HO, where the water activity is greater than about 0.4; stirring the mixture at room temperature; filtering the mixture to obtain a filter cake; washing the filter cake with distilled water; and removing the water to obtain berberine ursodeoxycholic acid Form A.

[0038] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form B. The method includes forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with acetonitrile / HO, where the acetonitrile:HO (v / v) is about 1:2 to about 2:1; and removing the acetonitrile / HO by slow evaporation to obtain berberine ursodeoxycholic acid Form B.

[0039] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form C. The method includes forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with isopropyl alcohol / isopropyl acetate, where the isopropyl alcohol:isopropyl acetate (v / v) is about 1:2 to about 2:1, and removing the isopropyl alcohol / isopropyl acetate by slow evaporation to obtain berberine ursodeoxycholic acid Form C.

[0040] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form D. The method includes forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with an organic solvent or organic solvent / water co-solvent having a water activity of less than about 0.2; stirring the mixture at room temperature; and filtering the mixture to obtain berberine ursodeoxycholic acid Form D.

[0041] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form E. The method includes providing berberine ursodeoxycholic acid Form A; and performing solid vapor diffusion in a dichloromethane atmosphere to obtain berberine ursodeoxycholic acid Form E.

[0042] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form H. The method includes the steps of dissolving crystalline and / or amorphous forms of berberine ursodeoxycholic acid in acetonitrile / HO, where acetonitrile:HO (v / v) is about 1:2 to about 2:1; slowly evaporating the acetonitrile / HO; collecting the precipitate by filtration; heating the resulting precipitate to about 100°C; and cooling the heated precipitate to room temperature to obtain berberine ursodeoxycholic acid Form H.

[0043] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form I. The method includes dissolving crystalline and / or amorphous forms of berberine ursodeoxycholic acid in tetrahydrofuran / HO, where tetrahydrofuran:HO (v / v) is about 1:2 to about 2:1; slowly evaporating the tetrahydrofuran / HO; and collecting the precipitate by filtration to obtain berberine ursodeoxycholic acid Form I.

[0044] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form J. The method includes the steps of providing berberine ursodeoxycholic acid Form A; heating berberine ursodeoxycholic acid Form A to about 100°C in N2; and cooling the heated berberine ursodeoxycholic acid to room temperature under N2 to obtain berberine ursodeoxycholic acid Form J.

[0045] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form P. The method includes the steps of providing berberine ursodeoxycholic acid Form A; slurrying berberine ursodeoxycholic acid Form A in MeOH / methyl ethyl ketone or MeOH / methyl tert-butyl ether, where MeOH:methyl ethyl ketone (v / v) is about 1:8 to about 1:10, or MeOH:methyl tert-butyl ether (v / v) is about 1:8 to about 1:10, at about 50° C.; and collecting the solid to obtain berberine ursodeoxycholic acid Form P.

[0046] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form W. The method includes the steps of providing berberine ursodeoxycholic acid Form A; slurrying berberine ursodeoxycholic acid Form A in cyclohexanone / n-butyl acetate, where cyclohexanone:n-butyl acetate (v / v) is about 1:3 to about 1:5 at room temperature; and collecting the solid to obtain berberine ursodeoxycholic acid Form W.

[0047] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form X. The method includes the steps of providing berberine ursodeoxycholic acid Form A; dissolving berberine ursodeoxycholic acid Form A in n-butanol; slowly evaporating the n-butanol at room temperature; and collecting the precipitate by filtration to obtain berberine ursodeoxycholic acid Form X. [Brief explanation of the drawings]

[0048] [Figure 1] 1 shows an embodiment of an XRPD pattern of Form A of BBR-UDCA. [Figure 2] 1 shows an embodiment of an XRPD pattern of Form B of BBR-UDCA. [Figure 3] 1 shows an embodiment of an XRPD pattern of Form C of BBR-UDCA. [Figure 4] 1 shows an embodiment of an XRPD pattern of Form D of BBR-UDCA. [Figure 5] 1 shows an embodiment of an XRPD pattern of Form E of BBR-UDCA. [Figure 6] 1 shows an embodiment of an XRPD pattern of Form H of BBR-UDCA. [Figure 7] 1 shows an embodiment of an XRPD pattern of Form I of BBR-UDCA. [Figure 8] 1 shows an embodiment of an XRPD pattern of Form J of BBR-UDCA. [Figure 9]1 shows an embodiment of an XRPD pattern of form P of BBR-UDCA. [Figure 10] 1 shows an embodiment of an XRPD pattern of form W of BBR-UDCA. [Figure 11] 1 shows an embodiment of an XRPD pattern of form X of BBR-UDCA. [Figure 12] 1 shows an overlay of XRPD patterns of BBR-UDCA Form A and a single crystal of the hemi-nonehydrate of BBR-UDCA. [Figure 13] 1 shows an overlay of XRPD patterns of Form A of BBR-UDCA after stability evaluation. [Figure 14] 1 shows an overlay of the XRPD pattern of Form D of BBR-UDCA after stability evaluation. [Figure 15] 1 shows an embodiment of a DVS graph of Form A of BBR-UDCA. [Figure 16] 1 shows an embodiment of an overlay of XRPD patterns of BBR-UDCA Form A before and after DVS testing. [Figure 17] 1 shows an embodiment of a DVS graph of form D of BBR-UDCA. [Figure 18] 1 shows an overlay of the XRPD patterns of the residual solids after the solubility test. [Figure 19] 1 shows the unit cell of single crystalline form A of BBR-UDCA. [Figure 20] 1 shows an embodiment of a TGA / DSC graph of Form B of BBR-UDCA. [Figure 21] 1 shows an embodiment of a TGA / DSC graph of Form C of BBR-UDCA. [Figure 22] 1 shows an embodiment of a TGA / DSC graph of Form D of BBR-UDCA. [Figure 23] 1 shows an embodiment of a TGA / DSC graph of Form H of BBR-UDCA. [Figure 24] 1 shows an embodiment of a TGA / DSC graph of Form I of BBR-UDCA. [Figure 25] 1 shows an embodiment of a TGA / DSC graph of Form P of BBR-UDCA. [Figure 26] 1 shows an embodiment of a TGA / DSC graph of form W of BBR-UDCA. [Figure 27] 1 shows an embodiment of a TGA / DSC graph of Form X of BBR-UDCA. [Figure 28] 1 shows an embodiment of a TGA graph of Form A of BBR-UDCA. [Figure 29] 1 shows an embodiment of a micrograph of single crystalline Form A of BBR-UDCA. [Figure 30] 1 shows an embodiment of the 1H NMR spectrum of BBR-UDCA Form A (bottom) and BBR-UDCA Form B (top). [Figure 31] 1 shows an embodiment of the 1H NMR spectrum of BBR-UDCA Form A (bottom) and BBR-UDCA Form C (top). [Figure 32] 1 shows an embodiment of the 1H NMR spectrum of BBR-UDCA form A (bottom) and BBR-UDCA form H (top). [Figure 33] 1 shows an embodiment of the 1H NMR spectrum of BBR-UDCA Form A (bottom) and BBR-UDCA Form I (top). [Figure 34] 1 shows an embodiment of a H NMR spectrum of form W of BBR-UDCA. [Figure 35] 1 shows an embodiment of a H NMR spectrum of form X of BBR-UDCA. DETAILED DESCRIPTION OF THE INVENTION

[0049] <Definition> Terms used herein have their ordinary meaning, and the meaning of such terms is independent at each occurrence. Nevertheless, unless otherwise stated, the following definitions apply throughout the specification and claims.

[0050] As used herein, the term "essentially the same" with respect to X-ray diffraction peak positions means that typical peak position and intensity variability is taken into account. For example, those skilled in the art will understand that peak positions (2θ) typically exhibit some degree of variability, typically on the order of 0.1 to 0.2°, depending on the instrument used to measure the diffraction. Furthermore, those skilled in the art will understand that relative peak intensities exhibit instrument-to-instrument variability as well as variability due to crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and are to be used only as a qualitative measure. Similarly, as used herein, "essentially the same" with respect to differential scanning calorimetry (DSC) is also intended to encompass the variability associated with these analytical techniques known to those skilled in the art.

[0051] As used herein, the term "stable" refers to a compound that remains substantially unchanged when exposed to conditions that enable its production, detection, recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound remains substantially unchanged when kept at a temperature of 40°C or less in the absence of moisture or other chemically reactive conditions for at least one week, preferably at least one month, more preferably at least six months, and even more preferably at least one year.

[0052] The term "solvate" as used herein refers to a crystalline solid adduct containing a stoichiometric or non-stoichiometric amount of solvent incorporated within the crystalline structure. When the solvent is tightly bound to the drug, the resulting complex has a well-defined stoichiometry that is independent of humidity. However, when the solvent is weakly bound, such as in channel solvates or hygroscopic compounds, the solvent content depends on humidity and drying conditions. In such cases, the complex is often non-stoichiometric. When the incorporated solvent is water, such an adduct is called a "hydrate." Thus, the term "hydrate" refers to a solvate containing a drug substance and stoichiometric or non-stoichiometric amounts of water.

[0053] The compound of the present invention is preferably isolated and purified after its preparation to obtain a composition with a weight percentage of 95% or more, which is then used or formulated as described herein.In certain embodiments, the compound of the present invention is more than 99% pure.As used herein, the term "substantially pure" in relation to a particular crystalline or amorphous form means that the crystalline or amorphous form contains less than 10% by weight, preferably less than 5%, more preferably less than 3%, and even more preferably less than 1% of any other physical form of the compound.

[0054] As used herein, the term "crystalline" refers to any solid material that exhibits three-dimensional order and, in contrast to amorphous solid materials, gives a distinctive X-ray powder diffraction (XRPD) pattern with well-defined peaks.

[0055] As used herein, the term "amorphous" refers to any solid material lacking three-dimensional order. In some cases, amorphous solids are characterized by known techniques, including X-ray powder diffraction (XRPD) crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or a combination of these techniques. Amorphous solids typically give diffuse XRPD patterns consisting of one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or greater).

[0056] As used herein, the term "polymorph" refers to different crystalline forms of the same compound, and includes, but is not limited to, other solid state molecular forms, including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.

[0057] As used herein, the term "X-ray powder diffraction pattern" or "XRPD pattern" refers to an experimentally observed diffractogram or parameters derived therefrom. An X-ray powder diffraction pattern is characterized by peak positions (abscissa) and peak intensities (ordinate).

[0058] As used herein, the term "2-theta value" or "2θ" refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, which is the common abscissa unit of a diffraction pattern. The experimental setup requires that the reflected beam be recorded at an angle 2-theta (2θ) if the reflection is diffracted when the incident beam forms an angle theta (θ) with a specific lattice plane. References herein to specific 2θ values ​​of a particular solid form are intended to refer to the 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, CuKα (wavelengths: λ1 = 1.540598 Å, λ2 = 1.544426 Å, intensity ratio λ2 / λ1 = 0.50) was used as the radiation source.

[0059] As used herein, the term "effective amount" of an active agent refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the patient.

[0060] As used herein, the term "treating, alleviating, or preventing a disease or disorder" refers to ameliorating such a condition before or after it occurs. The degree of such reduction or prevention, as measured by standard techniques, is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% when compared to an equivalent untreated control.

[0061] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0062] As used herein, "sufficient amount" refers to the amount of compound, alone or in combination with another treatment regimen, required to treat, prevent, or alleviate metabolic disorders such as diabetes in a clinically relevant manner. The sufficient amount of active compound used to practice the present invention for therapeutic treatment of a condition varies depending on the method of administration, age, weight, and general health of the mammal or patient. Ultimately, the prescriber will determine the appropriate amount and administration schedule. In addition, an effective amount may be the amount of compound that is safe and effective in treating patients as determined and approved by regulatory authorities (such as the U.S. Food and Drug Administration).

[0063] As used herein, a "low dose" refers to a dose that is at least 5% (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) less than the lowest standard recommended dose of a particular compound formulated for a given route of administration for the treatment of any human disease or condition. For example, a low dose of a drug that lowers glucose levels and is formulated for administration by inhalation will differ from a low dose of the same drug formulated for oral administration.

[0064] As used herein, "high dose" means at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) more than the highest standard recommended dose of a particular compound for the treatment of any human disease or condition.

[0065] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0066] <Detailed Description of the Invention> The present invention is based, in part, on the unexpected discovery of novel solid forms (e.g., crystalline forms) of berberine ursodeoxycholic acid (BBR-UDCA) that have one or more desirable properties, such as high stability, high crystallinity, high purity, low hygroscopicity, favorable dissolution, and / or favorable mechanical properties. In particular, the solid forms of BBR-UDCA disclosed herein offer improved physical stability and / or physicochemical properties that make them suitable for clinical research, product manufacturing, and therapeutic applications.

[0067] Multiple solid forms of BBR-UDCA have been identified, each of which can be uniquely identified by different analytical parameters, alone or in combination, including, but not limited to, X-ray powder diffraction pattern (XRPD) peaks or combinations of two or more peaks; thermogravimetric analysis (TGA); differential scanning calorimetry (DSC); dynamic vapor sorption (DVS); polarized light microscopy (PLM); high-performance liquid chromatography (HPLC); and nuclear magnetic resonance (NMR).

[0068] Diseases and disorders that can be treated and / or prevented by the compounds, pharmaceutical compositions, and methods disclosed herein include diabetes, diabetic complications, dyslipidemia, dyslipidemia in statin-intolerant patients, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, diabetic dyslipidemia, obesity, metabolic syndrome, prediabetes, atherosclerosis, heart disease, neurodegenerative disease, sarcopenia, muscle atrophy, inflammation, cancer, and liver diseases and conditions, such as fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cholestatic liver disease, or graft-versus-host disease of the liver. The compounds of the present invention are also useful for improving liver function in chronic viral-related liver disease and alcohol-related liver disease.

[0069] In one aspect, the present invention relates generally to a solid form of BBR-UDCA Form A, which has the following peaks: 3.98, 7.06, 7.34, 7.93, 8.79, 9.47, 11.70, 11.94, 12.34, 12.55, 13.90, 14.17, 15.14, 15.50, 16.16, 16.54, 16.78, 17.53, 17.06, 17.26, 17.66, 17.08, 17.29, 17.34, 17.93, 18.79, 18.47, 18.55, 18.66, 18.78, 18.53, 18.80, 18.90, 19.17, 20.14, 20.14, 20.50, 20.16, 20.54, 20.66, 20.78, 20.80, 20.90, 21.14, 21.14, 21.50, 21.16, 21.54, 21.78, 21.80, 21.90, 22.14, 22.14, 22.26, 22.34, 22.55, 23.90, 23.17, 23.14 ... and has an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 0.67, 18.23, 19.03, 19.98, 20.87, 21.13, 21.96, 23.49, 24.24, 24.97, 25.50, 26.63, 27.60, 28.06, 28.63, 29.40, and 30.49° (±0.2°).

[0070] In certain embodiments, the solid form (Form A of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 3.98, 7.06, 7.34, 8.79, and 16.54° (±0.2°).

[0071] In certain embodiments, the solid form (Form A of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 3.98, 7.06, 7.34, 8.79, 9.47, 11.94, 13.90, 14.17, 15.50, 16.16, 16.54, 16.78, and 17.67° (±0.2°).

[0072] In certain embodiments, the solid form (Form A of BBR-UDCA) is 3.98, 7.06, 7.34, 7.93, 8.79, 9.47, 11.70, 11.94, 12.34, 12.55, 13.90, 14.17, 15.14, 15.50, 16.16, 16.54, 16.78, 17.53, 17.67, 17.80, 18.00, 19.00, 20.00, 21.00, 22.00, 23.00, 24.00, 25.00, 26.00, 27.00, 28.00, 29.00, 30.00, 31.00, 32.0 It has an X-ray powder diffraction (XRPD) pattern containing peaks at 2θ values ​​of 8.23, 19.03, 19.98, 20.87, 21.13, 21.96, 23.49, 24.24, 24.97, 25.50, 26.63, 27.60, 28.06, 28.63, 29.40 and 30.49° (±0.2°).

[0073] In certain embodiments, the solid form (Form A of BBR-UDCA) is a hydrate of BBR-UDCA. In certain embodiments, the solid form (Form A of BBR-UDCA) is a hemi-nonehydrate of BBR-UDCA.

[0074] [ka]

[0075] In certain embodiments, the solid form (BBR-UDCA Form A) is crystalline. In certain embodiments, the crystalline form is characterized by a monoclinic system and a P21 space group. In certain embodiments of the crystalline form, each unit cell contains two asymmetric units, with two BBR cations, two UDCA anions, and nine HO molecules per asymmetric unit, and four BBR cations, four UDCA anions, and 18 HO molecules per unit cell (Figure 19).

[0076] In certain embodiments, the solid form (Form A of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0077] In certain embodiments, the solid form (Form A of BBR-UDCA) is characterized by a purity of 70% or greater.

[0078] In certain embodiments, the solid form (Form A of BBR-UDCA) is characterized by a purity of 95% or greater.

[0079] In another aspect, the invention generally relates to a solid form, Form B of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 7.39, 9.31, 12.41, 13.14, 14.37, 14.76, 15.53, 18.65, 21.79, 22.87, 25.27, 25.53, and 28.12° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0080] In certain embodiments, the solid form (Form B of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 9.31, 12.41, 15.53, 18.65, 21.79, 22.87, and 25.53° (±0.2°).

[0081] In certain embodiments, the solid form (Form B of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 7.39, 9.31, 12.41, 13.14, 14.37, 14.76, 15.53, 18.65, 21.79, 22.87, 25.27, 25.53, and 28.12° (±0.2°).

[0082] In certain embodiments, the solid form (Form B of BBR-UDCA) is a hydrate of berberine ursodeoxycholic acid.

[0083] In certain embodiments, the solid form (Form B of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0084] In certain embodiments, the solid form (Form B of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 78.1° C. (onset temperature) and an endotherm at about 91.2° C. (onset temperature).

[0085] In certain embodiments, the solid form (Form B of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0086] In certain embodiments, the solid form (Form B of BBR-UDCA) is characterized by a purity of 70% or greater.

[0087] In certain embodiments, the solid form (Form B of BBR-UDCA) is characterized by a purity of 95% or greater.

[0088] In yet another aspect, the invention generally relates to a solid form that is Form C of BBR-UDCA, which has an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 7.23, 10.42, 12.10, 13.37, 14.24, 14.48, 15.28, 15.95, 17.00, 18.17, 20.12, 21.77, and 25.47° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0089] In certain embodiments, the solid form (Form C of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 7.23, 12.10, 13.37, 15.28, 18.17, and 21.77° (±0.2°).

[0090] In certain embodiments, the solid form (Form C of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 7.23, 10.42, 12.10, 13.37, 14.24, 14.48, 15.28, 15.95, 17.00, 18.17, 20.12, 21.77, and 25.47° (±0.2°).

[0091] In certain embodiments, the solid form (Form C of BBR-UDCA) is a hydrate of berberine ursodeoxycholic acid.

[0092] In certain embodiments, the solid form (Form C of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0093] In certain embodiments, the solid form (Form C of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 68.4°C (onset temperature) and an endotherm at about 183.3°C (onset temperature).

[0094] In certain embodiments, the solid form (Form C of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0095] In certain embodiments, the solid form (Form C of BBR-UDCA) is characterized by a purity of 70% or greater.

[0096] In certain embodiments, the solid form (Form C of BBR-UDCA) is characterized by a purity of 95% or greater.

[0097] In yet another aspect, the invention generally relates to a solid form, Form D of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 4.24, 6.79, 8.50, 10.25, 11.50, 13.62, 14.74, 15.20, 17.92, 18.39, 22.91, and 25.73° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0098] In certain embodiments, the solid form (Form D of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 4.24, 6.79, 8.50, 13.62, and 15.20° (±0.2°).

[0099] In certain embodiments, the solid form (Form D of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 4.24, 6.79, 8.50, 10.25, 11.50, 13.62, 14.74, 15.20, 17.92, and 25.73°±(0.2°).

[0100] In certain embodiments, the solid form (Form D of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 4.24, 6.79, 8.50, 10.25, 11.50, 13.62, 14.74, 15.20, 17.92, 18.39, 22.91, and 25.73° (±0.2°).

[0101] In certain embodiments, the solid form (Form D of BBR-UDCA) is anhydroberberine ursodeoxycholic acid.

[0102] In certain embodiments, the solid form (Form D of BBR-UDCA) is crystalline.

[0103] In certain embodiments, the solid form (Form D of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0104] In certain embodiments, the solid form (Form D of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve that includes an endotherm at about 185.2° C. (onset temperature).

[0105] In certain embodiments, the solid form (Form D of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0106] In certain embodiments, the solid form (Form D of BBR-UDCA) is characterized by a purity of 70% or greater.

[0107] In certain embodiments, the solid form (Form D of BBR-UDCA) is characterized by a purity of 95% or greater.

[0108] In yet another aspect, the present invention relates generally to a solid form of BBR-UDCA Form E, which is a soluble solid form of BBR-UDCA, having the following peaks: 8.59, 10.55, 11.36, 11.86, 12.46, 13.08, 13.38, 14.34, 15.57, 17.24, 17.72, 18.43, 19.66, 19.84, 20.35, 20.65, 21.00, 22.00, 23.00, 24.00, 25.00, 26.00, 27.00, 28.00, 29.00, 30.00, 31.00, 32.00, 33.00, 34.00, 35.00, 36.00, 37.00, 38.00, 39.00, 40.00, 41.00, 42.00, 43.00, 44.00, 45.00, 46.00, 47.00, 48.00, 49.00, 50.00, 51.00, 52.00, 53.00, 54.00, 55.00, 56.00, 57.00, 58.00, 59.00, 60.00, 61.00, 62.00, 63.00, 64.00, 65.00, 66.00, 67.00, 68.00, 69.00, 70.00, 71.00, and 36.06° (±0.2°).

[0109] In certain embodiments, the solid form (Form E of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 11.36, 17.24, 17.72, and 20.91° (±0.2°).

[0110] In certain embodiments, the solid form (Form E of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 10.55, 11.36, 12.46, 13.08, 13.38, 14.34, 17.24, 17.72, 19.66, 19.84, 20.35, 20.91, 21.36, and 21.95° (±0.2°).

[0111] In certain embodiments, the solid form (Form E of BBR-UDCA) exhibited the following peaks: 8.59, 10.55, 11.36, 11.86, 12.46, 13.08, 13.38, 14.34, 15.57, 17.24, 17.72, 18.43, 19.66, 19.84, obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50). , having an X-ray powder diffraction (XRPD) pattern containing peaks at 2θ values ​​of 20.35, 20.91, 21.36, 21.95, 23.21, 24.67, 25.04, 25.82, 26.12, 27.01, 27.84, 28.97, 30.35, 33.33, 34.54, and 36.06° (±0.2°).

[0112] In certain embodiments, the solid form (Form E of BBR-UDCA) is crystalline.

[0113] In certain embodiments, the solid form (Form E of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0114] In certain embodiments, the solid form (Form E of BBR-UDCA) is characterized by a purity of 70% or greater.

[0115] In certain embodiments, the solid form (Form E of BBR-UDCA) is characterized by a purity of 95% or greater.

[0116] In yet another aspect, the invention generally relates to a solid form, Form H, of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 13.05, 14.63, and 25.46° (±0.2°) obtained using Cu Kα radiation (λ=1.540598 Å, λ=1.544426 Å, intensity ratio λ / λ=0.50).

[0117] In certain embodiments, the solid form (Form H of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 13.05, 14.63, and 25.46° (±0.2°).

[0118] In certain embodiments, the solid form (Form H of BBR-UDCA) is a hydrate of berberine ursodeoxycholic acid.

[0119] In certain embodiments, the solid form (Form H of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0120] In certain embodiments, the solid form (Form H of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 97.1° C. (peak temperature) and an endotherm at about 138.3° C. (onset temperature).

[0121] In certain embodiments, the solid form (Form H of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0122] In certain embodiments, the solid form (Form H of BBR-UDCA) is characterized by a purity of 70% or greater.

[0123] In certain embodiments, the solid form (Form H of BBR-UDCA) is characterized by a purity of 95% or greater.

[0124] In yet another aspect, the invention generally relates to a solid form that is Form I of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 4.19, 7.64, 10.03, 13.32, 13.84, 14.83, 16.73, 22.73, 25.61, and 28.57° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0125] In certain embodiments, the solid form (Form I of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 7.64, 10.03, 13.32, 16.73, and 22.73° (±0.2°).

[0126] In certain embodiments, the solid form (Form I of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 4.19, 7.64, 10.03, 13.32, 13.84, 14.83, 16.73, 22.73, 25.61, and 28.57° (±0.2°).

[0127] In certain embodiments, the solid form (Form I of BBR-UDCA) is a hydrate of berberine ursodeoxycholic acid.

[0128] In certain embodiments, the solid form (Form I of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0129] In certain embodiments, the solid form (Form I of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 56.2°C (onset temperature) and an endotherm at about 79.6°C (onset temperature).

[0130] In certain embodiments, the solid form (Form I of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0131] In certain embodiments, the solid form (Form I of BBR-UDCA) is characterized by a purity of 70% or greater.

[0132] In certain embodiments, the solid form (Form I of BBR-UDCA) is characterized by a purity of 95% or greater.

[0133] In yet another aspect, the present invention generally relates to a solid form of BBR-UDCA Form J, which is a Cu having an X-ray powder diffraction (XRPD) pattern obtained using Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50) and including one or more peaks at 2θ values ​​selected from the group consisting of 4.61, 6.32, 7.38, 8.22, 9.21, 10.57, 11.73, 12.13, 12.62, 12.96, 13.87, 14.55, 14.78, 15.81, 16.48, 17.69, 18.39, 19.01, 20.06, 21.25, 22.13, 23.20, 24.47, 24.89, 26.31, 27.98, 30.25, and 33.35° (±0.2°).

[0134] In certain embodiments, the solid form (Form J of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 4.61, 10.57, 14.78, 19.01, and 26.31° (±0.2°).

[0135] In certain embodiments, the solid form (Form J of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 4.61, 7.38, 8.22, 9.21, 10.57, 14.55, 14.78, 16.48, 17.69, 19.01, 20.06, 24.47, and 26.31° (±0.2°).

[0136] In certain embodiments, the solid form (Form J of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 4.61, 6.32, 7.38, 8.22, 9.21, 10.57, 11.73, 12.13, 12.62, 12.96, 13.87, 14.55, 14.78, 15.81, 16.48, 17.69, 18.39, 19.01, 20.06, 21.25, 22.13, 23.20, 24.47, 24.89, 26.31, 27.98, 30.25, and 33.35° (±0.2°).

[0137] In certain embodiments, the solid form (Form J of BBR-UDCA) is berberine ursodeoxycholic acid anhydride.

[0138] In certain embodiments, the solid form (Form J of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0139] In certain embodiments, the solid form (Form J of BBR-UDCA) is characterized by a purity of 70% or greater.

[0140] In certain embodiments, the solid form (Form J of BBR-UDCA) is characterized by a purity of 95% or greater.

[0141] In yet another aspect, the invention generally relates to a solid form, Form P, of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 3.11, 5.01, 5.78, 7.26, 9.20, 10.10, 10.79, 11.65, 13.70, 14.59, 15.22, 16.19, 16.54, 17.05, 18.06, 18.68, 20.52, 21.09, 21.73, 22.49, 24.73, 25.42, 25.94, and 30.11° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0142] In certain embodiments, the solid form (Form P of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 5.01, 5.78, 11.65, 17.05, 18.68, and 20.52° (±0.2°).

[0143] In certain embodiments, the solid form (Form P of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 5.01, 5.78, 7.26, 9.20, 10.10, 10.79, 11.65, 13.70, 14.59, 15.22, 16.19, 16.54, 17.05, 18.68, 20.52, and 25.94° (±0.2°).

[0144] In certain embodiments, the solid form (Form P of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 3.11, 5.01, 5.78, 7.26, 9.20, 10.10, 10.79, 11.65, 13.70, 14.59, 15.22, 16.19, 16.54, 17.05, 18.06, 18.68, 20.52, 21.09, 21.73, 22.49, 24.73, 25.42, 25.94, and 30.11° (±0.2°).

[0145] In certain embodiments, the solid form (Form P of BBR-UDCA) is a hydrate of berberine ursodeoxycholic acid.

[0146] In certain embodiments, the solid form (Form P of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0147] In certain embodiments, the solid form (Form P of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 100.3°C (peak temperature), an endotherm at about 122.5°C (peak temperature), and an endotherm at about 168.7°C (peak temperature).

[0148] In certain embodiments, the solid form (Form P of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0149] In certain embodiments, the solid form (Form P of BBR-UDCA) is characterized by a purity of 70% or greater.

[0150] In certain embodiments, the solid form (Form P of BBR-UDCA) is characterized by a purity of 95% or greater.

[0151] In yet another aspect, the invention generally relates to a solid form, Form W of BBR-UDCA, having an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at 2θ values ​​selected from the group consisting of 6.49, 7.16, 8.51, 10.21, 12.01, 13.13, 13.90, 14.42, 15.18, 15.57, 16.03, 16.45, 16.74, 17.08, 17.85, 18.39, 19.61, 20.43, 21.39, 21.70, 23.51, and 25.21° (±0.2°) obtained using Cu Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50).

[0152] In certain embodiments, the solid form (Form W of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 6.49, 7.16, 12.01, 13.13, 15.18, 16.45, 17.85, 21.39, and 25.21 degrees (±0.2 degrees).

[0153] In certain embodiments, the solid form (Form W of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 6.49, 7.16, 8.51, 10.21, 12.01, 13.13, 13.90, 14.42, 15.18, 15.57, 16.03, 16.45, 16.74, 17.08, 17.85, 18.39, 19.61, 20.43, 21.39, 21.70, 23.51, and 25.21° (±0.2°).

[0154] In certain embodiments, the solid form (Form W of BBR-UDCA) is a hydrate of berberine ursodeoxycholic acid.

[0155] In certain embodiments, the solid form (Form W of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0156] In certain embodiments, the solid form (Form W of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 82.1°C (peak temperature) and an endotherm at about 106.4°C (peak temperature).

[0157] In certain embodiments, the solid form (Form W of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0158] In certain embodiments, the solid form (Form W of BBR-UDCA) is characterized by a purity of 70% or greater.

[0159] In certain embodiments, the solid form (Form W of BBR-UDCA) is characterized by a purity of 95% or greater.

[0160] In yet another aspect, the present invention generally relates to a solid form of BBR-UDCA Form X, which is a Cu having an X-ray powder diffraction (XRPD) pattern obtained using Kα radiation (λ1=1.540598 Å, λ2=1.544426 Å, intensity ratio λ2 / λ1=0.50) which includes one or more peaks at 2θ values ​​selected from the group consisting of 3.63, 6.61, 7.24, 10.49, 11.95, 13.51, 14.26, 14.54, 15.14, 16.01, 16.82, 18.28, 20.26, 21.08, 21.49, 21.90, 25.60, 26.40, 27.31, 29.34, 30.59, 31.01, 34.04, 34.68 and 36.91° (±0.2°).

[0161] In certain embodiments, the solid form (Form X of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 3.63, 7.24, 11.95, 13.51, 14.54, 15.14, 18.28, 21.90, and 25.60° (±0.2°).

[0162] In certain embodiments, the solid form (Form X of BBR-UDCA) has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 3.63, 6.61, 7.24, 10.49, 11.95, 13.51, 14.26, 14.54, 15.14, 16.01, 16.82, 18.28, 20.26, 21.08, 21.49, 21.90, 25.60, 26.40, 27.31, 29.34, 30.59, 31.01, 34.04, 34.68, and 36.91° (±0.2°).

[0163] In certain embodiments, the solid form (Form X of BBR-UDCA) is a hydrate of berberine ursodeoxycholic acid.

[0164] In certain embodiments, the solid form (Form X of BBR-UDCA) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ essentially the same as those presented in FIG.

[0165] In certain embodiments, the solid form (Form X of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 86.7°C (peak temperature) and an endotherm at about 189.1°C (peak temperature).

[0166] In certain embodiments, the solid form (Form X of BBR-UDCA) is characterized by a differential scanning calorimetry (DSC) curve essentially the same as that presented in FIG.

[0167] In certain embodiments, the solid form (Form X of BBR-UDCA) is characterized by a purity of 70% or greater.

[0168] In certain embodiments, the solid form (Form X of BBR-UDCA) is characterized by a purity of 95% or greater.

[0169] In yet another aspect, the present invention generally relates to a solid form of berberine ursodeoxycholic acid hemi-nonehydrate.

[0170] In yet another aspect, the invention generally relates to compositions comprising one or more solid forms disclosed herein (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X).

[0171] In yet another aspect, the invention generally relates to compositions comprising two or more solid forms disclosed herein (e.g., two or more of Forms A, B, C, D, E, H, I, J, P, W, and X).

[0172] Compositions comprising one or more (or two or more) solid forms disclosed herein can optionally include additional pharmaceutical agents.

[0173] In certain embodiments, the composition further comprises one or more other therapeutically effective agents in addition to berberine ursodeoxycholic acid.

[0174] In certain embodiments, the composition further comprises one or more agents selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate, and vanadium.

[0175] In certain embodiments, the composition further comprises one or more agents selected from the group consisting of omega-3 fatty acids, S-adenosylmethionine, N-acetylcysteine, silymarin, polyenylphosphatidylcholine, and resveratrol.

[0176] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form A of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0177] In yet another aspect, the invention generally relates to pharmaceutical compositions comprising Form B of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0178] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form C of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0179] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form D of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0180] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form E of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0181] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising BBR-UDCA Form H and a pharmaceutically acceptable excipient, carrier, or diluent.

[0182] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form I of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0183] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising BBR-UDCA Form J and a pharmaceutically acceptable excipient, carrier, or diluent.

[0184] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising BBR-UDCA Form P and a pharmaceutically acceptable excipient, carrier, or diluent.

[0185] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising BBR-UDCA Form W and a pharmaceutically acceptable excipient, carrier, or diluent.

[0186] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Form X of BBR-UDCA and a pharmaceutically acceptable excipient, carrier, or diluent.

[0187] In certain embodiments, the pharmaceutical composition comprises one or more solid forms disclosed herein (e.g., one or more of forms A, B, C, D, E, H, I, J, P, W, and X).

[0188] In certain embodiments, the pharmaceutical composition comprises two or more solid forms disclosed herein (e.g., two or more of forms A, B, C, D, E, H, I, J, P, W, and X).

[0189] In certain embodiments, the pharmaceutical composition further comprises one or more other therapeutically effective agents in addition to berberine ursodeoxycholic acid.

[0190] In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more agents selected from the group consisting of vitamin D, vitamin C, vitamin E, vitamin B12, vitamin A, benfotiamine, chromium picolinate, and vanadium.

[0191] In certain embodiments, the pharmaceutical compositions of the present invention further comprise one or more agents selected from the group consisting of omega-3 fatty acids, S-adenosylmethionine, N-acetylcysteine, silymarin, polyenylphosphatidylcholine, and resveratrol.

[0192] In yet another aspect, the invention generally relates to unit dosage forms that include the pharmaceutical compositions disclosed herein.

[0193] In certain embodiments, the unit dosage form is an oral dosage form.

[0194] Any suitable dosage form may be utilized. In certain embodiments, the unit dosage form is a tablet. In certain embodiments, the unit dosage form is a capsule. In certain embodiments, the unit dosage form is a specific amount of a suspension.

[0195] In certain embodiments, the present invention provides a tablet comprising any of the solid forms or pharmaceutical compositions of BBR-UDCA disclosed herein. For example, in one embodiment, the tablet comprises about 1 to about 1,000 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X). Further, for example, the tablet comprises about 50 to about 500 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X). Even further, for example, the tablet comprises about 500 to 1,000 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X). Further still, for example, the tablet contains about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X).

[0196] In certain embodiments, the present invention provides a soft gelatin capsule containing a solid form of BBR-UDCA or any of the pharmaceutical compositions disclosed herein. For example, in one embodiment, the soft gelatin capsule contains about 1 to about 1,000 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X). For example, the soft gelatin capsule contains about 50 to about 500 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X). For example, the soft gelatin capsule contains about 500 to 1,000 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X). Further still, for example, a soft gelatin capsule contains about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg of a solid form of BBR-UDCA (e.g., one or more of Forms A, B, C, D, E, H, I, J, P, W, and X).

[0197] In yet another aspect, the present invention generally relates to a method of treating, alleviating, or preventing a metabolic disorder, cardiac disease, neurodegenerative disease, or liver disease, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0198] In yet another aspect, the present invention generally relates to a method for treating, alleviating, or preventing a disease or disorder in a mammal, including a human, effective to treat, prevent, or alleviate one or more diseases or disorders selected from fatty liver, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), cholestatic liver disease, hepatic graft-versus-host disease, primary sclerosing cholangitis, chronic virus-related liver disease, alcohol-related liver disease, prediabetes, diabetes, hyperlipidemia, hypercholesterolemia, diabetic dyslipidemia, dyslipidemia in statin-intolerant patients, obesity, or a disease or disorder related thereto, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition or unit dosage form disclosed herein.

[0199] In certain embodiments, the disease or disorder is cholestatic liver disease, hepatic graft-versus-host disease, chronic viral-related liver disease or alcohol-related liver disease, or a related disease or disorder.

[0200] In certain embodiments, the disease or disorder is fatty liver, NAFLD or NASH, or a related disease or disorder.

[0201] In certain embodiments, the disease or disorder is NAFLD or a related disease or disorder.

[0202] In certain embodiments, the disease or disorder is NASH or a related disease or disorder.

[0203] In certain embodiments, the disease or disorder is primary sclerosing cholangitis or a related disease or disorder.

[0204] In certain embodiments, the disease or disorder is hypercholesterolemia or a related disease or disorder.

[0205] In certain embodiments, the disease or disorder is prediabetes, diabetes or hyperlipidemia, diabetic dyslipidemia, or dyslipidemia, or an associated disease or disorder in a statin intolerant patient.

[0206] In certain embodiments, the disease or disorder is obesity or a related disease or disorder.

[0207] In certain embodiments, a subject is administered one or more other therapeutically effective agents in addition to berberine ursodeoxycholic acid.

[0208] In certain embodiments, the present invention relates to a solid form of BBR-UDCA, wherein the solid form is non-hygroscopic.

[0209] In certain embodiments, the present invention relates to a solid form of BBR-UDCA, wherein the solid form is anhydrous.

[0210] In certain embodiments, the present invention relates to a solid form of BBR-UDCA, wherein the solid form comprises a plurality of small crystallites of BBR-UDCA.

[0211] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form A. The method includes the steps of forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with an organic solvent and a co-solvent of HO, wherein the water activity is greater than about 0.4; stirring the mixture at room temperature; filtering the mixture to obtain a filter cake; washing the filter cake with distilled water; and removing the water to obtain berberine ursodeoxycholic acid Form A.

[0212] In certain embodiments, the organic solvent is EtOH.

[0213] In certain embodiments, the EtOH:HO (v / v) ratio is about 1:5 to about 1:30. In certain embodiments, the EtOH:HO (v / v) ratio is about 1:10 to about 1:20. In certain embodiments, the EtOH:HO (v / v) ratio is about 1:10.

[0214] In certain embodiments, the mixture is stirred at room temperature for about 1 to about 24 hours. In certain embodiments, the mixture is stirred at room temperature for about 2 to about 7 hours. In certain embodiments, the mixture is stirred at room temperature for about 3 to about 5 hours.

[0215] In certain embodiments, to obtain berberine ursodeoxycholic acid Form A, water is removed until the water content is about 10% or less.

[0216] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form B. The method includes forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with acetonitrile / HO, where the acetonitrile:HO (v / v) is about 1:2 to about 2:1, and removing the acetonitrile / HO by slow evaporation to obtain berberine ursodeoxycholic acid Form B.

[0217] In certain embodiments, the acetonitrile:H2O (v / v) is about 1:1.

[0218] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form C. The method includes forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with isopropyl alcohol / isopropyl acetate, where the isopropyl alcohol:isopropyl acetate (v / v) is about 1:2 to about 2:1, and removing the isopropyl alcohol / isopropyl acetate by slow evaporation to obtain berberine ursodeoxycholic acid Form C.

[0219] In certain embodiments, the ratio of isopropyl alcohol:isopropyl acetate (v / v) is about 1:1.

[0220] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form D. The method includes forming a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid with an organic solvent or organic solvent / water co-solvent having a water activity of less than about 0.2; stirring the mixture at room temperature; and filtering the mixture to obtain berberine ursodeoxycholic acid Form D.

[0221] In certain embodiments, a mixture of crystalline and / or amorphous forms of berberine ursodeoxycholic acid and ethyl acetate is formed.

[0222] In certain embodiments, the mixture is stirred at room temperature for about 1 to about 24 hours. In certain embodiments, the mixture is stirred at room temperature for about 2 to about 7 hours. In certain embodiments, the mixture is stirred at room temperature for about 3 to about 5 hours.

[0223] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form E. The method includes providing berberine ursodeoxycholic acid Form A and performing solid vapor diffusion in a dichloromethane atmosphere to obtain berberine ursodeoxycholic acid Form E.

[0224] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form H. The method includes the steps of dissolving crystalline and / or amorphous forms of berberine ursodeoxycholic acid in acetonitrile / HO, where acetonitrile:HO (v / v) is about 1:2 to about 2:1; slowly evaporating the acetonitrile / HO; heating the resulting precipitate to about 100°C; and cooling the heated precipitate to room temperature to obtain berberine ursodeoxycholic acid Form H.

[0225] In certain embodiments, the acetonitrile:H2O (v / v) is about 1:1.

[0226] In certain embodiments, the resulting precipitate is heated for about 0.5 to about 2 hours.

[0227] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form I. The method includes the steps of dissolving crystalline and / or amorphous berberine ursodeoxycholic acid in tetrahydrofuran / HO, where tetrahydrofuran:HO (v / v) is about 1:2 to about 2:1; slowly evaporating the tetrahydrofuran / HO; and collecting the precipitate by filtration to obtain berberine ursodeoxycholic acid Form I.

[0228] In certain embodiments, the ratio of tetrahydrofuran:H2O (v / v) is about 1:1.

[0229] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form J. The method includes the steps of providing berberine ursodeoxycholic acid Form A; heating berberine ursodeoxycholic acid Form A to about 100°C in N2; and cooling the heated berberine ursodeoxycholic acid to room temperature under N2 to obtain berberine ursodeoxycholic acid Form J.

[0230] In certain embodiments, berberine ursodeoxycholic acid Form A is heated in N2 for about 0.5 to about 2 hours.

[0231] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form P. The method includes the steps of providing berberine ursodeoxycholic acid Form A; slurrying berberine ursodeoxycholic acid Form A in MeOH / methyl ethyl ketone or MeOH / methyl tert-butyl ether, where MeOH:methyl ethyl ketone (v / v) is about 1:8 to about 1:10, or MeOH:methyl tert-butyl ether (v / v) is about 1:8 to about 1:10, at about 50° C.; and collecting the solid to obtain berberine ursodeoxycholic acid Form P.

[0232] In certain embodiments, the slurrying is carried out for about 6 to about 36 hours.

[0233] In certain embodiments, the MeOH:methyl tert-butyl ether (v / v) is 1:9.

[0234] In certain embodiments, MeOH:methyl ethyl ketone (v / v) is 1:9.

[0235] In yet another aspect, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form W. The method includes the steps of providing berberine ursodeoxycholic acid Form A; slurrying berberine ursodeoxycholic acid Form A in cyclohexanone / n-butyl acetate, where cyclohexanone:n-butyl acetate (v / v) is about 1:3 to about 1:5 at room temperature; and collecting the solids to obtain berberine ursodeoxycholic acid Form W.

[0236] In certain embodiments, the ratio of cyclohexanone:n-butyl acetate (v / v) is about 1:4.

[0237] In certain embodiments, the slurrying is carried out for about 6 to about 36 hours.

[0238] In yet another embodiment, the present invention generally relates to a method for preparing berberine ursodeoxycholic acid Form X. The method includes the steps of providing berberine ursodeoxycholic acid Form A; dissolving berberine ursodeoxycholic acid Form A in n-butanol; slowly evaporating the n-butanol at room temperature; and collecting the precipitate by filtration to obtain berberine ursodeoxycholic acid Form X.

[0239] In certain embodiments, evaporation of n-butanol at room temperature is carried out for about 6 to about 36 hours.

[0240] In a further aspect, the present invention contemplates that any one of the solid forms of BBR-UDCA disclosed herein can exist in the presence of any other physical form or mixture thereof. Thus, in one embodiment, the present invention provides a crystalline or amorphous form of BBR-UDCA described herein, or a pharmaceutical composition comprising a crystalline or amorphous form of BBR-UDCA, wherein the crystalline or amorphous form is present in a solid form comprising less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight of any other physical form of BBR-UDCA. For example, one embodiment is a solid form of BBR-UDCA comprising a crystalline form of BBR-UDCA having any one of the powder X-ray diffraction patterns disclosed herein, wherein the solid form contains less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3, or less than 1% by weight of any other physical form of BBR-UDCA.

[0241] In certain embodiments, the present invention relates to any of the above-mentioned forms of BBR-UDCA, wherein the form is substantially pure (ie, a substantially pure crystalline form or a substantially pure amorphous form).

[0242] A further aspect of the present invention provides a pharmaceutical composition comprising a crystalline or amorphous form of BBR-UDCA disclosed herein. In a further aspect, the present invention provides a pharmaceutical composition comprising a crystalline or amorphous form of BBR-UDCA disclosed herein, wherein the crystalline or amorphous form is substantially pure. In a further aspect, the present invention provides a method for preparing a pharmaceutical composition, comprising combining a crystalline or amorphous form of BBR-UDCA disclosed herein with a pharmaceutically acceptable excipient, carrier, or diluent. In a further aspect, the present invention provides a method for preparing a pharmaceutical composition, comprising combining a crystalline or amorphous form of BBR-UDCA disclosed herein with a pharmaceutically acceptable excipient, carrier, or diluent, wherein the crystalline or amorphous form is substantially pure. In a further aspect, the present invention provides a pharmaceutical composition prepared by combining a crystalline or amorphous form of BBR-UDCA disclosed herein with a pharmaceutically acceptable excipient, carrier, or diluent. In a further aspect, the present invention provides a pharmaceutical composition prepared by combining a crystalline or amorphous form of BBR-UDCA disclosed herein with a pharmaceutically acceptable excipient, carrier, or diluent, wherein the crystalline or amorphous form is substantially pure. In a further aspect, the present invention provides an oral dosage form comprising a crystalline or amorphous form of BBR-UDCA or a pharmaceutical composition disclosed herein. For example, in one embodiment, the oral dosage form is a tablet or capsule.

[0243] Isotopically labeled compound is also within the scope of the present disclosure.As used herein, " isotope-labeled compound " refers to the compound of the present disclosure, in which one or more atoms are replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is usually found in nature, and includes its pharmaceutical salts and prodrugs as described herein, respectively.The examples of isotopes that can be incorporated into the compounds of the present disclosure include, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O.17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as Cl.

[0244] By isotopically labeling the compounds disclosed herein, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) compounds and carbon-14( 14 C) labeled compounds are particularly preferred due to their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can confer certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances. Isotopically labeled compounds disclosed herein, including pharmaceutical salts, esters, and prodrugs, can be prepared by any means known in the art.

[0245] Furthermore, the normally abundant hydrogen ( 1 Substitution of hydrogen (H) with heavier isotopes, such as deuterium, can provide certain therapeutic benefits, resulting, for example, from improved absorption, distribution, metabolism, and / or excretion (ADME) properties, potentially creating drugs with improved efficacy, safety, and / or tolerability. 12 C 13 There may also be cases where substitution with C provides advantages. See WO 2007 / 005643, WO 2007 / 005644, WO 2007 / 016361, and WO 2007 / 016431.

[0246] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the presently disclosed compounds, as well as racemates, diastereomers and other mixtures of such isomers, are within the scope of this disclosure.

[0247] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0248] Possible formulations include those suitable for oral, sublingual, buccal, parenteral (e.g., subcutaneous, intramuscular, or intravenous), rectal, transdermal, intranasal, and topical administration, including inhalation administration. The most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the treatment being used, and the nature of the active compound.

[0249] Isomeric mixtures containing any of a variety of isomeric ratios can be utilized in accordance with the present invention. For example, when combining only two isomers, mixtures containing isomeric ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomeric mixtures.

[0250] The following examples are meant to be illustrative of the practice of the present invention and are not intended to be limiting in any way. [Example]

[0251] The following examples, including their preparation and analysis, further illustrate and exemplify certain aspects and embodiments of the present invention. It is to be understood that the scope of the present invention is not limited by the scope of the following examples.

[0252] <General Method 1. X-ray Powder Diffraction (XRPD)> XRPD data were collected according to the following general protocol.

[0253] Equipment Method XRPD patterns were collected on a PANalytical X-ray powder diffractometer equipped with an automatic sample changer, a theta-theta goniometer, an automatic beam divergence slit, and a PSD Vantec-1 detector. The X-ray tube voltage and current were set to 45 kV and 40 mA, respectively. The diffractometer was calibrated, and a calibration check was performed using a corundum standard on the day of data collection. The XRPD parameters used are listed in Table 1. Data were collected and analyzed using the software Data Viewer.

[0254] [Table 1]

[0255] <General Method 2. Single Crystal X-ray Diffraction (SCXRD)> SCXRD data were collected using a BRUKER D8 VENTURE diffractometer (Mo / Kα radiation, λ = 0.710 Å) at 153 K. Polarized light micrographs were taken using a Shanghai Cewei PXS9-T stereomicroscope.

[0256] <General Method 3. Differential Scanning Calorimetry (DSC)> DSC was performed using a TA Instruments TA Q200 / Q2000. The detailed parameters used are listed in Table 2.

[0257] [Table 2]

[0258] <General method 4. Thermogravimetric analysis (TGA)> TGA data were collected using a TA Instruments TA Q500 / Q5000 TGA. The detailed parameters used are listed in Table 3.

[0259] [Table 3]

[0260] <General Method 5. Dynamic Vapor Sorption (DVS)> DVS was measured via SMS (Surface Measurement System) DVS built-in. The DVS test parameters are listed in Table 4.

[0261] [Table 4]

[0262] <General Method 6. Solution Nuclear Magnetic Resonance (NMR)> Solution NMR was collected on a Bruker 400M NMR spectrometer using DMSO-d6.

[0263] <General Method 7. High Performance Liquid Chromatography (HPLC)> An Agilent 1260 / 1100 HPLC was utilized and the detailed chromatographic conditions for purity and solubility determination are listed in Table 5.

[0264] [Table 5]

[0265] [Table 6]

[0266] <Berberine Ursodeoxycholic Acid Form A> Preparation and characterization of Form A

[0267] 5 g of BBR-UDCA (mixed crystalline or amorphous form) was added to 20 mL of EtOH / HO (1:10, v / v). The mixture was stirred at room temperature for 5 hours, and then the mixture was filtered. The filter cake was washed with distilled water. Form A (4.3 g) was obtained.

[0268] XRPD and TGA Analysis of Form A The XRPD (Figure 1) pattern contained peaks at 2θ values ​​of 3.98, 7.06, 7.34, 7.93, 8.79, 9.47, 11.70, 11.94, 12.34, 12.55, 13.90, 14.17, 15.14, 15.50, 16.16, 16.54, 16.78, 17.53, 17.67, 18.23, 19.03, 19.98, 20.87, 21.13, 21.96, 23.49, 24.24, 24.97, 25.50, 26.63, 27.60, 28.06, 28.63, 29.40, and 30.49°. An XRPD overlay (Figure 12) showed that the experimental XRPD pattern for this sample was in good agreement with the calculated pattern derived from the single crystal structure, indicating that the sample was a hemi-nonahydrate. TGA data is shown in Figure 28. A weight loss of 9.4% was observed up to 100°C (theoretical weight loss for the hemi-nonahydrate was 10.0%).

[0269] <Berberine Ursodeoxycholic Acid Form B> Preparation and characterization of Form B 5 g of BBR-UDCA was dissolved in an ACN / HO (1:1, v / v) solution. Type B (1.6 g) was obtained by slow evaporation from the ACN / HO (1:1, v / v) solution.

[0270] XRPD, DSC and TGA Analysis of Form B The XRPD (Figure 2) pattern contained peaks at 2θ values ​​of 7.39, 9.31, 12.41, 13.14, 14.37, 14.76, 15.53, 18.65, 21.79, 22.87, 25.27, 25.53, and 28.12°. TGA / DSC data are shown in Figure 20. Upon heating to 150°C, a weight loss of 12.2% was observed. Two endotherms were observed at 78.1°C and 91.2°C (onset temperatures).

[0271] <Berberine Ursodeoxycholic Acid Form C> Preparation of Form C Type C of BBR-UDCA (1.8 g) was obtained by slow evaporation from a solution of 5 g of BBR-UDCA in isopropyl alcohol / isopropyl acetate (IPA / IPAc) (1:1, v / v).

[0272] XRPD, DSC and TGA Analysis of Form C The XRPD (Figure 3) pattern contained peaks at 2θ values ​​of 7.23, 10.42, 12.10, 13.37, 14.24, 14.48, 15.28, 15.95, 17.00, 18.17, 20.12, 21.77, and 25.47°. TGA / DSC data (Figure 21) showed a weight loss of 11.6% upon heating to 150°C, with two endotherms at 68.4°C and 183.3°C (onset temperatures).

[0273] <Berberine Ursodeoxycholic Acid Form D> Preparation of Form D 5 g of BBR-UDCA Form A was added to ethyl acetate (aw≦0.2). The resulting suspension was stirred at room temperature for 5 hours, and then the mixture was filtered. BBR-UDCA Form D (4.3 g) was obtained.

[0274] XRPD, DSC and TGA Analysis of Form D The XRPD (Figure 4) pattern contained peaks at 2θ values ​​of 4.24, 6.79, 8.50, 10.25, 11.50, 13.62, 14.74, 15.20, 17.92, 18.39, 22.91, and 25.73°. The TGA / DSC data (Figure 22) showed a 2.2% weight loss and an endotherm at 185.2°C (onset temperature) after heating to 150°C.

[0275] <Berberine Ursodeoxycholic Acid Form E> Preparation of Form E 5 g of BBR-UDCA Form A was added to a dichloromethane (DCM) atmosphere. Type E (4.5 g) was obtained by solid vapor diffusion in DCM after 24 hours.

[0276] XRPD, DSC and TGA Analysis of Form E The XRPD (Figure 5) pattern contained peaks at 2θ values ​​of 8.59, 10.55, 11.36, 11.86, 12.46, 13.08, 13.38, 14.34, 15.57, 17.24, 17.72, 18.43, 19.66, 19.84, 20.35, 20.91, 21.36, 21.95, 23.21, 24.67, 25.04, 25.82, 26.12, 27.01, 27.84, 28.97, 30.35, 33.33, 34.54, and 36.06°.

[0277] <Berberine Ursodeoxycholic Acid Form H> Preparation of Form H 5 g of BBR-UDCA was dissolved in acetonitrile / HO (1:1, v / v). After slow evaporation of the solvent, the precipitate was collected by filtration. The resulting solid was heated to 100°C for 0.5-2 hours and then cooled to room temperature. Form H of BBR-UDCA (0.8 g) was obtained.

[0278] XRPD, DSC and TGA analysis of Form H The XRPD (Figure 6) pattern contained peaks at 2θ values ​​of 13.05, 14.63, and 25.46°. The TGA / DSC data (Figure 23) showed a weight loss of 7.9% after heating to 150°C, with an endotherm (peak temperature) of 97.1°C and an endotherm (onset temperature) of 138.3°C.

[0279] <Berberine Ursodeoxycholic Acid Form I> Preparation of Form I 5 g of BBR-UDCA was dissolved in tetrahydrofuran / HO (1:1, v / v). After the solvent was slowly evaporated for 24 hours, the precipitate was collected by filtration. Form I of BBR-UDCA (0.9 g) was obtained.

[0280] XRPD, DSC and TGA analysis of Form I The XRPD (Figure 7) pattern contained peaks at 2θ values ​​of 4.19, 7.64, 10.03, 13.32, 13.84, 14.83, 16.73, 22.73, 25.61, and 28.57°. The TGA / DSC data (Figure 24) showed a weight loss of 10.7% after heating to 150°C, an endotherm at 56.2°C (onset temperature) and an endotherm at 79.6°C (onset temperature).

[0281] <Berberine Ursodeoxycholic Acid Form J> Preparation of Form J 5 g of BBR-UDCA form A was heated to 100° C. under N for 0.5-2 hours, then cooled to room temperature with N protection to obtain BBR-UDCA form J (4.4 g).

[0282] XRPD, DSC and TGA analysis of Form J The XRPD (Figure 8) pattern contained peaks at 2θ values ​​of 4.61, 6.32, 7.38, 8.22, 9.21, 10.57, 11.73, 12.13, 12.62, 12.96, 13.87, 14.55, 14.78, 15.81, 16.48, 17.69, 18.39, 19.01, 20.06, 21.25, 22.13, 23.20, 24.47, 24.89, 26.31, 27.98, 30.25, and 33.35°. Form J converts to Form A upon exposure to air.

[0283] <Berberine Ursodeoxycholic Acid Form P> Preparation of Form P BBR-UDCA form P (3.8 g) was obtained by slurrying 5 g of BBR-UDCA form A in MeOH / methyl ethyl ketone (1:9, v / v) at 50° C. for 1 day.

[0284] XRPD, DSC and TGA analysis of Form P The XRPD (Figure 9) pattern contained peaks at 2θ values ​​of 3.11, 5.01, 5.78, 7.26, 9.20, 10.10, 10.79, 11.65, 13.70, 14.59, 15.22, 16.19, 16.54, 17.05, 18.06, 18.68, 20.52, 21.09, 21.73, 22.49, 24.73, 25.42, 25.94, and 30.11°. TGA / DSC data (Figure 25) showed an 8.8% weight loss after heating to 150°C, with an endotherm at 100.3°C (peak temperature), an endotherm at 122.5°C (peak temperature), and an endotherm at 168.7°C (peak temperature).

[0285] <Berberine Ursodeoxycholic Acid Form W> Preparation of Form W BBR-UDCA form W (4.0 g) was obtained by slurrying 5.0 g of BBR-UDCA form A in cyclohexanone / n-butyl acetate (1:4, v / v) at room temperature for 1 day.

[0286] XRPD, DSC and TGA analysis of Form W The XRPD (Figure 10) pattern contained peaks at 6.49, 7.16, 8.51, 10.21, 12.01, 13.13, 13.90, 14.42, 15.18, 15.57, 16.03, 16.45, 16.74, 17.08, 17.85, 18.39, 19.61, 20.43, 21.39, 21.70, 23.51, and 25.21 degrees 2θ. The TGA / DSC data (Figure 26) showed a 7.2% weight loss after heating to 110°C, with an endotherm at 82.1°C (peak temperature) and an endotherm at 106.4°C (peak temperature).

[0287] <Berberine Ursodeoxycholic Acid Form X> Preparation of Form X 5 g of BBR-UDCA Form A was dissolved in n-butanol. After slowly evaporating the solvent at room temperature for 24 hours, the precipitate was collected by filtration. BBR-UDCA Form X (0.8 g) was obtained.

[0288] XRPD, DSC and TGA Analysis of Form X The XRPD (Figure 11) pattern contained peaks at 3.63, 6.61, 7.24, 10.49, 11.95, 13.51, 14.26, 14.54, 15.14, 16.01, 16.82, 18.28, 20.26, 21.08, 21.49, 21.90, 25.60, 26.40, 27.31, 29.34, 30.59, 31.01, 34.04, 34.68, and 36.91 degrees 2θ. The TGA / DSC data (Figure 27) showed a weight loss of 17.0% after heating to 140°C, and an endotherm at 86.7°C (peak temperature) and 189.1°C (peak temperature) were observed.

[0289] <Stability evaluation> To evaluate the physical and chemical stability of BBR-UDCA Form A and BBR-UDCA Form D, samples were stored at 80°C (sealed) for 24 hours and at 25°C / 60% RH (open) and 40°C / 75% RH (open) for one week. Both samples were characterized using XRPD and HPLC, and the results are summarized in the following table. The XRPD results, shown in Figures 13 and 14, showed no change in crystalline morphology for both Forms A and D under all three conditions. Based on the one-week stability results at 25°C / 60% RH (open) and 40°C / 75% RH (open), the physical stability of Form A was superior to that of Form D.

[0290] HPLC-DAD results showed that under all three conditions, no decrease in HPLC purity was observed for Form A, and a decrease in purity (0.5-1.7 area %) was observed for Form D, indicating slight degradation of Form D.

[0291] [Table 7]

[0292] Samples of BBR-UDCA Form A, BBR-UDCA Form D, and BBR-UDCA (mixed crystals without quality control of crystal form) were stored at 25°C / 60% RH (with sealing) and 40°C / 75% RH (with sealing) for one month. All samples were characterized using XRPD and HPLC, and the results are summarized in the table below. Under all three conditions, there was no change in the crystal form for both Form A and Form D. Both Form A and Form D showed better chemical stability compared to the mixed crystals of BBR-UDCA.

[0293] [Table 8]

[0294] <Evaluation of moisture absorption> Dynamic vapor sorption (DVS) isotherm plots of BBR-UDCA Form A were collected at 25°C under various humidity conditions: 60%RH-95%RH-0%RH-95%RH (ambient humidity was 60%). The results are shown in Figure 15. As the DVS plot shows, a step-like weight loss was observed between 10%RH and 20%RH. A water uptake of 9.9% was observed at 25°C / 80%RH, which was consistent with the weight loss from TGA. The XRPD overlay shown in Figure 16 indicates no change in crystalline morphology after DVS, indicating good physical stability of Form A.

[0295] To investigate the hygroscopicity of Form D of BBR-UDCA, a DVS isotherm plot of Form D was collected at 25°C from 0-95% RH. The results are shown in Figure 17. A water absorption of 4.1% was observed at 25°C / 80% RH, but a clear increase was observed above 90% RH, with a water absorption of 24.5% at 95% RH. The results of the DVS test indicated that Form D deliquesced at high humidity.

[0296] <Polarizing microscope (PLM)> To observe the morphology of the samples, PLM characterization was performed on BBR-UDCA Form A and BBR-UDCA Form D. Needle-shaped particles were observed in the Form A sample, with particle sizes ranging from 20 μm to 50 μm. For the Type D sample, the particle size was approximately 10 μm.

[0297] <Equilibrium water solubility> Approximately 5 mg of each crystalline solid (BBR-UDCA Form A and BBR-UDCA Form D, respectively) was weighed into separate 3 mL bottles, suspended in 1 mL of water, and slurried (1,000 rpm) at room temperature for 24 hours, followed by centrifugation at 10,000 rpm for 3 minutes. The resulting residual solids were characterized by XRPD, and the supernatants were analyzed by HPLC-DAD / ELSD. Due to the poor UV absorption of UDCA, DAD was used as the detector for BBR only, while ELSD was used for both BBR and UDCA. As shown in Figure 18, regardless of the initial crystalline form, the crystalline form of both residual solids after the solubility test was Form A, indicating that Form D converted to Form A during the solubility experiment. When Form A was used as the starting material, the solubility of BBR was 0.35 mg / mL or 0.33 mg / mL using DAD or ELSD as the detector, respectively. The solubility of UDCA was 0.42 mg / mL, indicating a molar ratio of 0.94:1 (BBR:UDCA). When Form D was used as the starting material, the solubility of BBR was 0.42 mg / mL or 0.41 mg / mL using a DAD or ELSD as the detector, respectively. The solubility of UDCA was 0.52 mg / mL, indicating a molar ratio of 0.93:1 (BBR:UDCA). The reason for the deviation from 1:1 may be that a small amount of imbalance occurred after HTD 1801 was dissolved in water, and its limited amount made it difficult to detect by XRPD.

[0298] According to these results, Form D exhibited better aqueous solubility than Form A.

[0299] [Table 9]

[0300] <Single crystal growth and structural analysis> Single crystals of the compound HTD1801 hemi-negahydrate were obtained by liquid vapor diffusion in an ACN / HO (1:5, v:v) / MTBE mixed solvent system. SCXRD characterization and structural analysis of the single crystal confirmed that it resided in the monoclinic system and the P21 space group. Each unit cell contains two asymmetric units, with two BBR cations, two UDCA anions, and nine HO molecules per asymmetric unit. This means that there are four BBR cations, four UDCA anions, and 18 HO molecules per unit cell. Adjacent UDCA anions and HO molecules are connected to each other to form a three-dimensional supramolecular framework structure with one-dimensional linear channels via intermolecular hydrogen bonds (OH··O). The BBR cations are stacked in an orderly fashion within the channels via π-π interactions, ultimately forming the 3-D crystal structure of the crystal.

[0301] [Table 10]

[0302] The XRPD overlay (FIG. 12) showed that the XRPD pattern of Form A was in good agreement with that of the obtained single crystal. Furthermore, the TGA data for Form A showed that a weight loss of 9.4% was observed, whereas the theoretical weight loss for the hemi-nonahydrate was 10.0%. All these results indicated that Form A is a hemi-nonahydrate of BBR-UDCA.

[0303] Applicant's disclosure is described herein in preferred embodiments with reference to the drawings, in which like numerals represent the same or similar elements. Reference throughout this specification to "one embodiment," "an embodiment," or similar terminology means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification all refer to the same embodiment, although not necessarily so.

[0304] The described features, structures, or characteristics of Applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, numerous specific details are set forth to provide a thorough understanding of embodiments of the present invention. However, one of ordinary skill in the art will recognize that Applicant's compositions and / or methods may be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations have not been shown or described in detail to avoid obscuring aspects of the disclosure.

[0305] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0306] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.Although any methods and materials similar or equivalent to those described herein can also be used to practice or test this disclosure, preferred methods and materials are described here.The methods recited herein can be carried out in any order that is logically possible, in addition to the specific order disclosed.

[0307] <Incorporated by reference> In this disclosure, references and citations have been made to other documents, such as patents, patent applications, patent publications, journals, books, papers, web content, etc. All such documents are incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated herein by reference but that contradicts existing definitions, statements, or other disclosure materials explicitly set forth herein is incorporated only to the extent that no contradiction arises between the incorporated material and the present disclosure material. In the event of a conflict, the conflict should be resolved in favor of this disclosure as the preferred disclosure.

[0308] <Equivalent> The representative examples disclosed herein are intended to help illustrate the invention and are not intended to, and should not be construed as, limiting the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of the specification, including the examples that follow and references to the scientific and patent literature cited herein. The foregoing examples contain important additional information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. Cu Kα radiation (λ １ =1.540598Å,λ ２ = 1.544426 Å, intensity ratio λ ２ / λ １ 1. A crystalline solid which is berberine ursodeoxycholic acid Form A, having an X-ray powder diffraction (XRPD) pattern containing peaks at 2θ values ​​of 7.06, 7.34, 8.79, 9.47, 11.94, 14.17, 15.50, 16.54, and 16.78° (±0.2°) obtained using a 2θ analyzer (Eq. (I) = 0.50); The berberine (BBR) ursodeoxycholic acid (UDCA) Form A is represented by the following chemical formula: 【Chemical 1】 The crystalline solid is characterized in that the purity of the crystalline solid is 95% or more.

2. 2. The crystalline solid of claim 1, having an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ values ​​of 3.98, 7.06, 7.34, 7.93, 8.79, 9.47, 11.70, 11.94, 12.34, 12.55, 13.90, 14.17, 15.14, 15.50, 16.16, 16.54, 16.78, 17.53, 17.67, 18.23, 19.03, 19.98, 20.87, 21.13, 21.96, 23.49, 24.24, 24.97, 25.50, 26.63, 27.60, 28.06, 28.63, 29.40 and 30.49° (±0.2°).

3. The crystalline solid is monoclinic and P2 １ 3. The crystalline solid of claim 1 or 2, characterized by a space group.

4. Each unit cell contains two asymmetric units, with two BBR cations, two UDCA anions, and nine H ２ O molecules are present, and there are four BBR cations, four UDCA anions, and 18 H per unit cell. ２ 4. The crystalline solid of claim 3, wherein O molecules are present.

5. A composition comprising the crystalline solid of any one of claims 1 to 4.

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