# Patent

## Title
Colchicine solid-state forms; methods of making; and methods of use thereof

## Abstract

Disclosed are new colchicine solid-state forms, methods of preparing the solid-state forms, as well as formulations prepared therefrom and uses thereof.

## Background
CROSS REFERENCE TO RELATED APPLICATION
This application is a divisional application of U.S. application Ser. No. 12/423,040 filed Apr. 14, 2009, which claims the benefit of U.S. Provisional Application Ser. No. 61/045,003 filed Apr. 15, 2008, each of which is hereby incorporated by reference in its entirety.


BACKGROUND
Colchicine, chemical name (−)-N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide, (N-((7S)-5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)-acetamide, IUPAC), CAS Registry No. 64-86-8 is a known gout suppressant.
Polymorphs are solid crystalline phases of an active agent differing by the arrangement of the active agent molecules in the solid state. An active agent may also exist in other solid-state forms such as a hydrate, a solvate, or an ansolvate. The active agent may also exist in a non-crystalline or amorphous form. Different solid-state forms of the same active agent can exhibit different physical properties such as solubilities, melting points, hardness, optical properties, dissolution, and the like. Differences in the dissolution of the solid-state forms can result in differences in the therapeutic activity between the different forms.
Polymorphism and solid-state properties is an important consideration in formulating an active agent, specifically in regard to solubility of the active agent and dissolution from a dosage formulation. Use of a particular solid-state form may provide superior solubility, dissolution, and possibly increased bioavailability.
There remains a need in the art for new colchicine solid-state forms and processes of preparing such forms.
SUMMARY
In one embodiment, a solid-state colchicine is colchicine Form B cyclohexane solvate.
In another embodiment, a solid-state colchicine is colchicine Form C hydrate or Form K hydrate.
In yet another embodiment, a solid-state colchicine is colchicine Form D ethanol solvate.
In still another embodiment, a solid-state colchicine is colchicine Form E ansolvate.
In one embodiment, a solid-state colchicine is colchicine Form F non-crystalline.
In another embodiment, a solid-state colchicine is colchicine Form G acetone solvate.
In yet another embodiment, a solid-state colchicine is colchicine Form H dioxane solvate.
In still another embodiment, a solid-state colchicine is colchicine Form I tetrahydrofuran solvate.
In one embodiment, a solid-state colchicine is colchicine Form J toluene solvate.
In another embodiment, a solid-state colchicine is colchicine Form L mesitylene solvate.
In one embodiment, a composition comprises a solid-state colchicine selected from the group consisting of Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, and a combination thereof; and a pharmaceutically acceptable excipient.
In another embodiment, a method of treating a patient comprises administering to a patient in need of colchicine therapy a composition comprising a solid-state colchicine selected from the group consisting of Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, and a combination thereof; and a pharmaceutically acceptable excipient.
Also disclosed are methods of preparing solid-state forms of colchicine Forms B, C, D, E, F, G, H, I, J, K, and L.
These and other embodiments, advantages and features of the present invention become clear when detailed description and examples are provided in subsequent sections.



BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 illustrates XRPD pattern of colchicine Form A.
FIG. 2 illustrates a FT-Raman spectrum of colchicine Form A.
FIG. 3 illustrates XRPD pattern of colchicine Form B.
FIG. 4 illustrates a FT-Raman spectrum of colchicine Form B.
FIG. 5 illustrates XRPD pattern of colchicine Form C.
FIG. 6 illustrates a FT-Raman spectrum of colchicine Form C.
FIG. 7A illustrates a DVS curve of colchicine Form C relative humidity/mass change versus time; and FIG. 7B illustrates a DVS curve of colchicine Form C mass change versus relative humidity).
FIG. 8 illustrates XRPD pattern of colchicine Form D.
FIG. 9 illustrates a FT-Raman spectrum of colchicine Form D.
FIG. 10 illustrates XRPD pattern of colchicine Form E.
FIG. 11 illustrates a FT-Raman spectrum of colchicine Form E.
FIG. 12 illustrates XRPD pattern of colchicine Form F.
FIG. 13 illustrates a FT-Raman spectrum of colchicine Form F.
FIG. 14 illustrates XRPD pattern of colchicine Form G.
FIG. 15 illustrates a FT-Raman spectrum of colchicine Form G.
FIG. 16 illustrates XRPD pattern of colchicine Form H.
FIG. 17 illustrates a FT-Raman spectrum of colchicine Form H.
FIG. 18 illustrates XRPD pattern of colchicine Form I.
FIG. 19 illustrates a FT-Raman spectrum of colchicine Form I.
FIG. 20 illustrates XRPD pattern of colchicine Form J.
FIG. 21 illustrates a FT-Raman spectrum of colchicine Form J.
FIG. 22 illustrates XRPD pattern of colchicine Form K.
FIG. 23 illustrates a FT-Raman spectrum of colchicine Form K.
FIG. 24 illustrates a FT-Raman spectrum of colchicine Form L.



DETAILED DESCRIPTION
Disclosed herein are novel solid-state forms of colchicine described herein as Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, and Form L. Known crystalline colchicine is designated as Form A, an ethyl acetate solvate containing 6.8% ethyl acetate. Also disclosed herein are methods of preparing the solid-state forms, compositions comprising the solid-state forms and methods of using the solid-state forms for treating a patient in need of colchicine therapy.
As used herein, “solid-state form” is inclusive of polymorphs, hydrates, solvates, ansolvates, and amorphous forms.
The solid-state forms of colchicine disclosed herein may be hydrated or solvated. The different forms may be characterized and differentiated on the basis of their X-ray powder diffraction (XRPD) peaks or FT-Raman peaks exemplified, for example, in the Tables in the Example section below. Solid state forms may also be differentiated by their melting point as determined by, for example, differential scanning calorimetry (DSC); by thermogravimetric analysis (TGA); by their FT-IR spectra; and by their crystalline unit cell parameters.
Colchicine Form B is a cyclohexane solvate. In one embodiment, colchicine Form B exhibits XRPD peak positions at 5.79, 10.50, 12.48, 14.73, 16.38, 17.47, 19.33, 19.78, 21.27, 22.57, 23.86, and 25.11±0.2 degrees 2-theta. In another embodiment, colchicine Form B exhibits the XRPD peak positions in Table 6 below. In yet another embodiment, colchicine Form B exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 3. In another embodiment, colchicine Form B exhibits Raman peaks at 2936, 1594, 1571, 1553, 1503, 1432, 1350, 1323, and 1286±2 cm−1. In another embodiment, colchicine Form B exhibits Raman peaks in Table 6 below. In another embodiment, colchicine Form B exhibits a Raman spectrum which is substantially similar to FIG. 4. Form B can contain about 4.5 to about 7.0% cyclohexane, specifically about 5.0 to about 6.6%, more specifically about 5.4 to about 6.0%, and yet more specifically about 5.6% cyclohexane.
Cochicine Form C is a hydrate. In one embodiment, colchicine Form C exhibits XRPD peak positions at 10.11, 11.69, 13.35, 15.55, 16.61, 17.58, 17.93, 18.34, 19.44, 21.00, 21.42, 24.23, 24.91, 25.96, 27.38, 28.05, and 28.87±0.2 degrees 2-theta. In another embodiment, colchicine Form C exhibits the XRPD peak positions in Table 8 below. In yet another embodiment, colchicine Form C exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 5. In another embodiment, colchicine Form C exhibits Raman peaks at 2930, 1597, 1544, 1500, 1434, 1350, 1323, 1285, and 1254±2 cm−1. In another embodiment, colchicine Form C exhibits Raman peaks in Table 8 below. In another embodiment, colchicine Form C exhibits a Raman spectrum which is substantially similar to FIG. 6. Not wishing to be bound by theory, colchicine C is likely a sesquihydrate. Form C can comprise about 5.5 to about 7.0% water, specifically about 5.8 to about 6.8, more specifically about 6.0 to about 6.5, and yet more specifically about 6.3% water. In one embodiment, Form C has a melting peak of about 115° C. by DSC analysis. In another embodiment, Form C is substantially free of solvent other than water.
Colchicine Form D is an ethanol solvate. In one embodiment, colchicine Form D exhibits XRPD peak positions at 9.45, 10.88, 13.63, 16.26, 18.31, 18.76, 21.16 and 25.10±0.2 degrees 2-theta. In another embodiment, colchicine Form D exhibits the XRPD peak positions in Table 10 below. In yet another embodiment, colchicine Form D exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 8. In another embodiment, colchicine Form D exhibits Raman peaks at 2933, 1588, 1569, 1549, 1501, 1443, 1436, 1352 and 1325±2 cm−1. In another embodiment, colchicine Form D exhibits Raman peaks in Table 10 below. In another embodiment, colchicine Form D exhibits a Raman spectrum which is substantially similar to FIG. 9. Form D can comprise about 9.0 to about 11% ethanol, specifically about 9.4 to about 10.7%, and more specifically about 10 to about 10.3% ethanol. In one embodiment, Form D has a melting peak of about 95° C. by DSC analysis.
Colchicine Form D can be desolvated by drying under an inert atmosphere (e.g., nitrogen, argon, and the like) or under vacuum. In one embodiment, the drying can occur at about room temperature, specifically about 15 to about 30° C., more specifically about 18 to about 25° C., and yet more specifically about 20 to about 22° C. The resulting solid-state form is likely Form E ansolvate.
Colchicine Form E is an ansolvent. In one embodiment, colchicine Form E exhibits XRPD peak positions at 8.16, 9.79, 11.76, 13.13, 13.81, 15.60, 16.16, 17.79, 19.64, 20.36, 20.88, 22.00, 22.59, 23.67, 24.75, and 26.90±0.2 degrees 2-theta. In another embodiment, colchicine Form E exhibits the XRPD peak positions in Table 12 below. In yet another embodiment, colchicine Form E exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 10. In another embodiment, colchicine Form E exhibits Raman peaks at 2933, 1577, 1503, 1429, 1350, 1324, and 1280±2 cm−1. In another embodiment, colchicine Form E exhibits Raman peaks in Table 12 below. In another embodiment, colchicine Form E exhibits a Raman spectrum which is substantially similar to FIG. 11. In one embodiment, Form E comprises about 0.00001% to about 2.5% solvent, specifically about 0.1 to about 2% solvent, and yet more specifically about 0.5 to about 1% solvent.
In one embodiment, colchicine Form F is a non-crystalline form of colchicine. In another embodiment, colchicine Form F exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 12. In another embodiment, colchicine Form F exhibits Raman peaks at 2934, 1586, 1504, 1430, 1351, 1323, and 1285±2 cm−1. In another embodiment, colchicine Form F exhibits Raman peaks in Table 15 below. In another embodiment, colchicine Form F exhibits a Raman spectrum which is substantially similar to FIG. 13. In one embodiment, colchicine Form F can contain water.
Colchicine Form G is an acetone solvate. In one embodiment, colchicine Form G exhibits XRPD peak positions at 9.39, 12.01, 12.41, 16.44, 18.87, 19.67, 20.94, 22.28, 23.82, and 25.59±0.2 degrees 2-theta. In another embodiment, colchicine Form G exhibits the XRPD peak positions in Table 17 below. In yet another embodiment, colchicine Form G exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 14. In another embodiment, colchicine Form G exhibits Raman peaks at 2935, 1596, 1559, 1504, 1431, 1347, 1323, and 1292±2 cm−1. In another embodiment, colchicine Form G exhibits Raman peaks in Table 17 below. In another embodiment, colchicine Form G exhibits a Raman spectrum which is substantially similar to FIG. 15. Form G can comprise about 10 to about 30% acetone, specifically about 12.7 to about 25% acetone, and more specifically about 15 to about 18.3% acetone. In one embodiment, Form G has a melting peak of about 87° C. by DSC analysis.
Colchicine Form H is a dioxane solvate. In one embodiment, colchicine Form H exhibits XRPD peak positions at 12.04, 13.32, 14.57, 15.78, 17.04, 18.05, 18.25, 20.35, 20.59, 22.00, 23.64, 24.13, and 24.35±0.2 degrees 2-theta. In another embodiment, colchicine Form H exhibits the XRPD peak positions in Table 19 below. In yet another embodiment, colchicine Form H exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 16. In another embodiment, colchicine Form H exhibits Raman peaks at 2940, 2846, 1573, 1503, 1442, 1430, 1353, 1324, and 1283±2 cm−1. In another embodiment, colchicine Form H exhibits Raman peaks in Table 19 below. In another embodiment, colchicine Form H exhibits a Raman spectrum which is substantially similar to FIG. 17. In one embodiment, Form H comprises about 13 to about 22% dioxane, specifically about 15 to about 20%, and more specifically about 16 to about 18.1% dioxane.
Colchicine Form I is a tetrahydrofuran solvate. In one embodiment, colchicine Form I exhibits XRPD peak positions at 5.84, 9.86, 10.64, 11.74, 14.77, 16.45, 17.61, 19.10, 19.96, 21.44, 23.94, 24.12, 24.47, and 25.10±0.2 degrees 2-theta. In another embodiment, colchicine Form I exhibits the XRPD peak positions in Table 21 below. In yet another embodiment, colchicine Form I exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 18. In another embodiment, colchicine Form I exhibits Raman peaks at 2939, 2840, 1594, 1569, 1553, 1503, 1433, 1350, 1323, and 1286±2 cm−1. In another embodiment, colchicine Form I exhibits Raman peaks in Table 21 below. In another embodiment, colchicine Form I exhibits a Raman spectrum which is substantially similar to FIG. 19. Form I can comprise about 5.0 to about 9.0% tetrahydrofuran, specifically about 5.7 to about 8.3%, and more specifically about 6.3 to about 7.0%.
Colchicine Form J is a toluene solvate. In one embodiment, colchicine Form J exhibits XRPD peak positions at 9.46, 10.43, 11.96, 13.27, 14.50, 15.67, 17.00, 18.10, 19.86, 20.43, 24.26, 25.62, 26.30, and 27.42±0.2 degrees 2-theta. In another embodiment, colchicine Form J exhibits the XRPD peak positions in Table 23 below. In yet another embodiment, colchicine Form J exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 20. In another embodiment, colchicine Form J exhibits Raman peaks at 3065, 2933, 1590, 1574, 1502, 1441, 1430, 1350, 1321, and 1283±2 cm−1. In another embodiment, colchicine Form J exhibits Raman peaks in Table 23 below. In another embodiment, colchicine Form J exhibits a Raman spectrum which is substantially similar to FIG. 21. Form J can comprise about 14.0 to about 19.5% toluene, specifically about 15.0 to about 9.0%, and more specifically about 16.3 to about 18.7% toluene.
Colchicine Form K is probably a hydrate. In one embodiment, colchicine Form K exhibits XRPD peak positions at 11.95, 13.48, 13.59, 17.84, 18.09, 18.52, 21.61, 23.78, 25.16 and 27.65±0.2 degrees 2-theta. In another embodiment, colchicine Form K exhibits the XRPD peak positions in Table 25 below. In yet another embodiment, colchicine Form K exhibits an X-ray powder diffraction pattern which is substantially similar to FIG. 22. In another embodiment, colchicine Form K exhibits Raman peaks at 2931, 1597, 1587, 1565, 1544, 1500, 1435, 1350, 1323, 1297, and 1254±2 cm−1. In another embodiment, colchicine Form K exhibits Raman peaks in Table 25 below. In another embodiment, colchicine Form K exhibits a Raman spectrum which is substantially similar to FIG. 23. Not wishing to be bound by theory, colchicine Form K is likely a dihydrate. Form K can comprise about 7.1 to about 9.0% water, specifically about 7.8 to about 8.7, more specifically about 8.0 to about 8.5, and yet more specifically about 8.3% water. In another embodiment, Form K is substantially free of solvent other than water.
Colchicine Form L is propably a mesitylene solvate. In one embodiment, colchicine Form L exhibits Raman peaks at 2935, 1591, 1570, 1553, 1503, 1432, 1349, 1323, and 1286±2 cm−1. In another embodiment, colchicine Form L exhibits Raman peaks in Table 27 below. In another embodiment, colchicine Form L exhibits a Raman spectrum which is substantially similar to FIG. 24. Colchicine Form L can contain about 4.0 to about 10.0% mesitylene, specifically about 4.8 to about 9.1%, and more specifically about 6.0 to about 7.0% mesitylene.
In one embodiment, the colchicine solid-state form is a solvate of an International Conference on Harmonisation (ICH) class 3 solvent. Exemplary ICH class 3 solvents include acetic acid, acetone, anisole (methoxybenzene), 1-butanol, 2-butanol, butyl acetate, tert-butylmethyl ether, cumene (isopropylbenzene(1-methyl)ethylbenzene), dimethyl sulfoxide (DMSO), ethanol, 2-ethoxyethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, n-heptane, isobutyl acetate, isopropyl acetate, isopropyl alcohol, methyl acetate, 3-methyl-1-butanol (isoamyl alcohol), methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol (isobutyl alcohol), n-pentane, 1-pentanol (amyl alcohol), and propyl acetate.
In one embodiment, the colchicine Form B, C, D, E, F, G, H, I, J, K or L is substantially free of impurities. “Substantially free of impurities” means a material comprises no more than about 4.0% total impurities, excluding any solvent that may be part of the specified solid-state form (e.g., for colchicine Form B cyclohexane solvate, cyclohexane is excluded as an impurity). In additional embodiments, the material comprises no more than about 3.0% total impurities, more specifically no more than about 2.0% total impurities, and yet more specifically no more than about 1.0% total impurities. Exemplary impurities include N-deacetyl-N-formyl colchicine (N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]formamide), β-Lumicolchicine (N-[(7S,7bR,10aS)-1,2,3,9-tetramethoxy-8-oxo-5,6,7,7b,8,10a-hexahydrobenzo[a]cyclopenta[3,4]cyclobuta[1,2-c]cyclohepten-7-yl]-acetamide), Colchicoside (N-[(7S,12aS)-3-(β-D-glucopyranosyloxy)-1,2,10-trimethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide), 3-O-demethyl colchicine (N-[(7S,12aS)-3-hydroxy-1,2,10-trimethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide), and colchiceine (N-[7S,12aS)-10-hydroxy-1,2,3-trimethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide).
The purity of the colchicine can be determined using a variety of techniques known in the art such as high pressure liquid chromatography (HPLC), and the like.
The solid-state forms of colchicine can be prepared using a variety of techniques including crystallization from solution and precipitation from solution using an antisolvent, suspension equilibration (“slurrying”), drying and water vapor adsorption, and evaporation. The foregoing processes, or any isolation step or drying step, can be carried out under ambient conditions or under an inert atmosphere (e.g., nitrogen, argon, and the like).
The starting colchicine material for the following processes can be any one of Forms A, B, C, D, E, F, G, H, I, J, K, L, a solvate, a hydrate, or a mixture thereof.
New processes of preparing colchicine include crystallization from a solvent system containing a single solvent or two or more solvents. Optionally, an anti-solvent can be used.
In a generalized procedure, colchicine is dissolved in a solvent system with optional heating to form a crystallization solution. In one embodiment, the heated solution can be at about the boiling point of the solvent system, specifically about 25 to about 100° C., more specifically about 30 to about 90° C., yet more specifically about 40 to about 80° C., and still yet more specifically about 50 to about 70° C.
The crystallization solution can be allowed to stand at ambient temperature or cooled to a lower temperature to allow crystal formation. In one embodiment, temperatures for crystal formation can be about −20 to about 25° C., specifically about −10 to about 20° C., more specifically about 0 to about 15° C., and yet more specifically about 3 to about 10° C.
The crystallization can be accomplished with slow cooling or rapid cooling. Rapid cooling can involve placing the crystallization solution under conditions of the targeted lower temperature without a gradual lowering of the temperature. In one embodiment, slow cooling can involve reducing the temperature of the crystallization solution at about 1 to about 30° C. per hour, specifically about 5 to about 25° C. per hour, and yet more specifically about 10 to about 20° C. per hour to a targeted lower temperature.
Optionally, the crystallization solution, prior to any solids formation, can be filtered to remove any undissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
In one embodiment, the crystallization solutions can be seeded with the desired solid-state form of colchicine.
Suitable solvents for preparing the solid-state forms of colchicine include those that do not adversely affect the stability of the colchicine, and are preferably inert. Suitable solvents may be organic, aqueous, or a mixture thereof. Suitable organic solvents may be an aqueous solvent such as water or water combined with a water miscible solvent; aliphatic hydrocarbons such as n-octane and cyclohexane; aliphatic alcohols such as methanol (MeOH), ethanol (EtOH), n-propanol, isopropanol (IPA), n-butanol, tert-amyl alcohol (t-AmOH); ethers such as tetrahydrofuran (THF), dioxane, methyl-tert-butyl ether, 1,2-dimethoxyethane (DME), and 2-methyl tetrahydrofuran; aliphatic ketones such as acetone, methyl ethyl ketone (MEK), and methyl isobutyl ketone; aliphatic carboxylic esters such as methyl acetate, ethyl acetate (EtOAc), and isopropyl acetate; aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene; aliphatic hydrocarbons such as hexane; aliphatic nitriles such as acetonitrile (MeCN); chlorinated hydrocarbons such as dichloromethane (DCM), chloroform, and carbon tetrachloride; aliphatic sulfoxides such as dimethyl sulfoxide (DMSO); amides such as dimethylformamide (DMF) and dimethylacetamide (DMA); organic acids such as acetic acid; N-methyl-2-pyrrolidone; pyridine; and the like, as well as mixtures comprising at least one of the foregoing organic solvents. Other solvents can be used as an anti-solvent to induce crystal formation of the colchicine from solution.
“Solvent system” means a single or a combination of two or more solvents.
In one embodiment, Form B can be prepared by dissolving colchicine in a mixture of cyclohexane and ethanol with optional heating. An amount of cyclohexane is added to the solution as an antisolvent such that Form B precipitates from solution. In one embodiment, the temperature of the mixture for the precipitation process can be about room temperature to about 80° C., specifically about to about 70° C., and yet more specifically about 40 to about 60° C. The starting colchicine can be Form A.
In one embodiment, Form D can be prepared by dissolving colchicine in a mixture of n-octane and ethanol with optional heating. An amount of n-octane is added to the solution as an antisolvent such that Form D precipitates from solution. The temperature of the mixture for the precipitation process can be about room temperature to about 80° C., specifically about 30 to about 70° C., and yet more specifically about 40 to about 60° C.
Suspension equilibration, or “slurrying”, as opposed to complete dissolution of colchicine in a solvent system, can be used to prepare a colchicine solid-state form. For example a suspension of colchicine can be prepared by combining colchicine and a solvent system wherein some of the colchicine is not fully dissolved. Solvents and solvent system as previously discussed can be applied here.
Processes of preparing colchicine include slurrying a mixture of colchicine and a solvent system containing a single solvent or two or more solvents. Optionally, an anti-solvent can be used. The volume of the solvent system used to prepare the slurry mixture is an amount such that the colchicine is not fully dissolved.
In one embodiment, the slurry mixture can be heated to about the boiling point of the solvent system, specifically about 25 to about 100° C., more specifically about 30 to about 90° C., yet more specifically about 40 to about 80° C., and still yet more specifically about 50 to about 70° C.
Optionally, slurry mixture can be allowed to stand at ambient temperature or cooled to a lower temperature to allow solid formation. In one embodiment, slurrying temperatures can be about −20 to about 25° C., specifically about −10 to about 20° C., more specifically about 0 to about 15° C., and yet more specifically about 3 to about 10° C.
The slurry mixture can initially be heated followed by slow cooling or rapid cooling. Rapid cooling can involve placing the slurry mixture under conditions of the targeted lower temperature without a gradual lowering of the temperature. In one embodiment, slow cooling can involve reducing the temperature of the slurry mixture at about 1 to about 30° C. per hour, specifically about 5 to about 25° C. per hour, and yet more specifically about 10 to about 20° C. per hour to a targeted lower temperature.
In one embodiment, the slurry mixture can be seeded with the desired solid-state form of colchicine.
Suitable solvents for preparing the solid-state forms of colchicine via slurrying include those discussed above.
Optionally, the slurry mixture can be sonicated.
In one embodiment, colchicine Form D is prepared by slurrying colchicine in ethanol, specifically cyclohexane/ethanol. In one embodiment, the slurrying can be performed at a temperature of about 0 to about 40° C., specifically about 10 to about 30° C. and yet more specifically about 20 to about 25° C. In another embodiment, the volume of the solvent system used to prepare the slurry mixture is an amount of about to about 100 mg to about 2 grams of colchicine per ml solvent, specifically about 200 mg to about 1 gram, and yet more specifically about 400 mg to about 800 mg per ml solvent. In one embodiment, the slurry mixture is seeded with Form D.
In one embodiment, colchicine Form G is prepared by slurrying colchicine in acetone. In one embodiment, the slurrying can be performed at a temperature of about 0 to about 40° C., specifically about 10 to about 30° C. and yet more specifically about 20 to about 25° C. In another embodiment, the volume of the solvent system used to prepare the slurry mixture is an amount of about to about 100 mg to about 1.5 grams of colchicine per ml solvent, specifically about 150 mg to about 1 gram, and yet more specifically about 200 mg to about 800 mg per ml solvent. In one embodiment, the slurry mixture is seeded with Form G.
In one embodiment, colchicine Form H is prepared by slurrying colchicine in 1,4-dioxane. in one embodiment, the slurrying can be performed at a temperature of about 0 to about 40° C., specifically about 10 to about 30° C. and yet more specifically about 20 to about 25° C. In another embodiment, the volume of the solvent system used to prepare the slurry mixture is an amount of about to about 100 mg to about 2 grams of colchicine per ml solvent, specifically about 200 mg to about 1 gram, and yet more specifically about 400 mg to about 800 mg per ml solvent. In one embodiment, the slurry mixture is seeded with Form H.
In one embodiment, colchicine Form I is prepared by slurrying colchicine in tetrahydrofuran. In one embodiment, the slurrying can be performed at a temperature of about 0 to about 40° C., specifically about 10 to about 30° C. and yet more specifically about 20 to about 25° C. In another embodiment, the volume of the solvent system used to prepare the slurry mixture is an amount of about to about 100 mg to about 2 grams of colchicine per ml solvent, specifically about 200 mg to about 1 gram, and yet more specifically about 400 mg to about 800 mg per ml solvent. In one embodiment, the slurry mixture is seeded with Form I.
In one embodiment, colchicine Form J is prepared by slurrying colchicine in toluene, specifically toluene/acetonitrile. In one embodiment, the slurrying can be performed at a temperature of about 0 to about 40° C., specifically about 10 to about 30° C. and yet more specifically about 20 to about 25° C. In another embodiment, the volume of the solvent system used to prepare the slurry mixture is an amount of about to about 100 mg to about 2 grams of colchicine per ml solvent, specifically about 200 mg to about 1 gram, and yet more specifically about 400 mg to about 800 mg per ml solvent. In one embodiment, the slurry mixture is seeded with Form J.
In the evaporation processes to prepare a colchicine solid-state form, colchicine can be dissolved in a solvent system and the solvent system can be allowed to evaporate until the colchicine solid-state form is formed. Heating or cooling as discussed previously can optionally be used. The solvent system can evaporate under vacuum conditions. Optionally, the evaporation can be accomplished under ambient conditions or under an inert atmosphere as discussed herein.
In one embodiment, colchicine Form C is prepared by suspending colchicine in 0.1 M tris(hydroxymethyl)-aminomethane solution and allowing the solvent to evaporate until Form C forms.
In one embodiment, Form K is prepared by suspending colchicine in 0.05 M tris(hydroxymethyl)-aminomethane buffer substance pH=7.4 and allowing the solvent to evaporate until Form K forms.
In the drying process, colchicine is placed under conditions to effect removal of any water or other solvent present. The removal can be accomplished under reduced pressure (e.g., vacuum) and optionally with heat.
In one embodiment, colchicine Form D is dried under nitrogen for a period of time sufficient to result in the conversion to colchicine Form E.
In one embodiment, colchicine Form C is prepared by exposing colchicine to greater than about 75% RH for a time sufficient to convert colchicine to Form C. In another embodiment, the colchicine starting material is slurried in water prior to isolation and subsequent exposure to greater than about 75% RH. The starting colchicine can be Form A, B, D, E, F, G, H, I, J, L or a colchicine solvate.
In any of the foregoing processes, the resulting solid colchicine can be isolated or dried under ambient conditions or under an inert atmosphere (e.g., nitrogen, argon, and the like). The drying can optionally be under vacuum. Furthermore, the drying can be accomplished with optional heating.
Also disclosed herein are pharmaceutical compositions comprising the colchicine solid-state forms prepared herein.
Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, powders, and granules. In such solid dosage forms, the solid complex may be admixed with one or more of the following: (a) one or more inert excipients (or carriers), such as sodium citrate or dicalcium phosphate; (b) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) solution retarders, such as paraffin; (g) absorption accelerators, such as quaternary ammonium compounds; (h) wetting agents, such as cetyl alcohol and glycerol monostearate; (i) adsorbents, such as kaolin and bentonite; and (j) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and combinations comprising one or more of the foregoing additives. For capsules and tablets, the dosage forms may also comprise buffering agents.
By “oral dosage form” is meant to include a unit dosage form for oral administration. An oral dosage form may optionally comprise a plurality of subunits such as, for example, microcapsules or microtablets. Multiple subunits may be packaged for administration in a single dose.
By “subunit” is meant to include a composition, mixture, particle, pellet, etc., that can provide an oral dosage form alone or when combined with other subunits.
The compositions can be immediate-release forms or controlled-release forms.
By “immediate-release” is meant a conventional or non-modified release in which greater then or equal to about 75% of the active agent is released within two hours of administration, specifically within one hour of administration.
By “controlled-release” is meant a dosage form in which the release of the active agent is controlled or modified over a period of time. Controlled can mean, for example, sustained-, delayed- or pulsed-release at a particular time. Alternatively, controlled can mean that the release of the active agent is extended for longer than it would be in an immediate-release dosage form, e.g., at least over several hours.
Dosage forms can be combination dosage forms having both immediate-release and controlled-release characteristics, for example, a combination of immediate-release pellets and controlled-release pellets. The immediate-release portion of a combination dosage form may be referred to as a loading dose.
Certain compositions described herein may be “coated”. The coating may be a suitable coating, such as, a functional or a non-functional coating, or multiple functional or non-functional coatings. By “functional coating” is meant to include a coating that modifies the release properties of the total composition, for example, a sustained-release coating. By “non-functional coating” is meant to include a coating that is not a functional coating, for example, a cosmetic coating. A non-functional coating can have some impact on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition.
Also disclosed are methods of treating a patient in need of colchicine therapy with the colchicine solid-state forms. The colchicine solid-state forms disclosed herein and compositions prepared therefrom can be used in prevention or treatment of various diseases or conditions, including, for example, attacks of acute gouty arthritis and pain in attacks of acute gouty arthritis, chronic gout (prophylaxis), a cystic disease, for example polycystic kidney disease or cystic fibrosis, a lentiviral infection, demyelinating diseases of central or peripheral origin, multiple sclerosis, cancer, an inflammatory disorder such as rheumatoid arthritis, glaucoma, Dupuytren's contracture, idiopathic pulmonary fibrosis, primary amyloidosis, recurrent pericarditis, acute pericarditis, asthma, postpericardiotomy syndrome, proliferative vitreoretinopathy, Behcet's disease, Familial Mediterranean fever, idiopathic thrombocytopenic purpura, primary biliary cirrhosis, and pyoderma gangrenosum, or in enhancing bone formation or bone mineral density.
The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
EXAMPLES
The following experimental procedures are used unless stated otherwise.
The X-ray powder diffraction (XRPD) patterns are recorded with a PANalytical X'Pert powder diffractometer (Copper Ku radiation). Sample holder: metallic, sample thickness 0.4 mm. The sample is covered with Kapton foil (resulting in a slightly higher background). For X-ray measurements a hermetically closed sample chamber is used. The XRPD patterns are shown in the 20 range from 2 to 400.
Fourier-transform Raman spectroscopy (FT-Raman) spectra are recorded on a Bruker RFS 100 FT-Raman system with a near infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. For each sample, 64 scans with a resolution of 4 cm−1 are accumulated. 300 mW laser power is used. Raman measurements are conducted using hermetically closed glass tubes. The FT-Raman data are shown in the region between 3200 to 100 cm−1. No peaks were measured from 3500 to 3200 cm−1.
Thermogravimetry coupled with Fourier-transform infrared spectroscopy (TG-FTIR): Thermo gravimetric measurements are carried out with a Netzsch Thermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector 22 or IFS 28 (sample pans with a pinhole, N2 atmosphere, heating rate 10 K/min, range 25° C. to 350° C.).
Dynamic vapor sorption (DVS): Sorption Measurement System SPS11-100n. The sample was placed in an Al crucible, and the sample was allowed to equilibrate at 75% relative humidity (RH) before starting a pre-defined humidity program.
1H-NMR: 1H-NMR spectra were recorded using a Bruker DPX300 spectrometer with a proton frequency of 300.13 MHz, a 30° excitation pulse, and a recycle delay of 1 s. 16 scans were accumulated, and CDCl3 was used as the solvent.
DSC: Differential scanning calorimetry was carried out with a Perkin Elmer DSC-7 instrument (closed gold sample pan or gold-plated steel sample pan; heating rates 10° C./min).
Example A
Characterization of Colchicine Form A, Ethyl Acetate Solvate
Colchicine Form A ethyl acetate solvate was analyzed by FT-Raman, XRPD and TG-FTIR and determined to be an ethyl acetate solvate containing about 6.8% ethyl acetate.
FIG. 1 illustrates an XRPD pattern of Form A with a peak listing provided in Table 1 below. FIG. 2 illustrates a FT-Raman spectrum and a peak listing is provided in Table 1.







TABLE 1







XRPD and FT-Raman peak 


table of colchicine Form A








XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












4.25
4
2968


5.82
10
2938


9.80
12
2840


10.58
56
1593


11.68
15
1569


12.37
17
1553


12.61
20
1503


12.94
15
1461


14.06
24
1432


14.89
41
1415


16.41
49
1382


16.84
34
1371


17.63
98
1350


18.07
20
1323


18.44
46
1285


19.04
33
—


19.45
46
—


19.96
61
—


20.23
35
—


21.03
27
—


21.44
51
—


21.70
28
—


22.70
49
—


23.08
27
—


23.57
31
—


23.91
64
—


24.15
100
—


24.40
47
—


24.97
42
—


25.43
64
—


26.14
34
—


26.96
22
—


27.45
21
—


27.85
25
—


28.53
31
—


28.81
21
—


29.67
22
—


30.12
38
—


31.28
19
—


32.33
23
—


32.81
24
—


33.18
16
—


33.81
17
—









TG-FTIR analysis reveals two stepwise weight losses for a total of 6.8% ethyl acetate, which are strongest at about 170 and about 240° C. This is typical for a solvate (3:1 colchicine to solvent). Decomposition is observed above 275° C.









TABLE 2





Temperature 
Mass loss
Released 


range
(%)
compound/comment







 25-200° C.
4.44
Ethyl acetate


200-275° C.
2.34
Ethyl acetate


275-350° C.
9.18
Decomposition









Example B
Screening Experiments
Five techniques are used to find colchicine solid forms: 1) suspension equilibration, 2) precipitation 3) drying and water vapor adsorption, 4) evaporation, and 5) melt quench. Suspension equilibration generally is carried out by slurrying the colchicine in a solvent system, optionally including an antisolvent. Precipitation generally is carried out by adding an antisolvent to a solution of colchicine. Evaporation technique is generally carried out by allowing the solvent of a solution of colchicine to evaporate to induce crystallization of the colchicine. Water vapor adsorption technique generally involves exposing colchicine to a controlled humid environment so that the material takes up water. The drying experiments can be performed under inert atmospheres (e.g., nitrogen). Melt quench generally involves fast cooling a melt to form a solid.







TABLE 3







Suspension equilibration results
















Time



Starting


Temperature
stirred
Outcome/


material
Process
Solvent
(° C.)
(days)
remarks





Form A
Slurry,
Water
Room temp.
2
Analyzed 



isolated;



by FT-



drying



Raman/







dried at 







0% RH


Form A
Slurry,
Water
Room temp.
2
Form C/



isolated;



dried at 



water vapor



75.5% 



adsorption



RH 3 







weeks


Form A
Slurry
Dioxane
Room temp.
2
Form H


Form A
Slurry
THF
Room temp.
2
Form I


Form A
Slurry
Acetone
Room temp.
2
Form G


Form A
Slurry
Toluene/
Room temp.
2
Form J




MeCN 3:1





Form A
Slurry
Cyclohexane/ 
Room temp.
2
Form D




EtOH







 4:1





Form D
Slurry
cyclohexane
Room temp.
2
Analyzed 







by FT-







Raman


Form A
Slurry
cyclohexane
Room temp.
2
Analyzed 







by FT-







Raman


Form A
Slurry
n-octane
110
1
Analyzed 







by FT-







Raman


Form A
Slurry
Cyclohexane/
Room temp.
1
Form D




EtOH







 4:1





Form A
Slurry
Cyclohexane/
Room temp.
1
Form D




EtOH







 4:1





Form D
Slurry
n-octane
Room temp.
3
Analyzed 





−110

by FT-







Raman;







amorphous


Form D
Slurry
mesitylene
Room temp.
3
Analyzed 





−110

by FT-







Raman


Form C
Slurry
water
1
2
Analyzed 







by FT-







Raman


Form C
Slurry
Acetone/
1-room
3
Analyzed 




water 1:1
temp.

by FT-







Raman


Form C
Slurry
n-octane
110
3
Analyzed 







by FT-







Raman


Form H
Slurry
n-octane
110
3
Amorphous


Form G
Slurry
n-octane
80
3
Analyzed 







by FT-







Raman


Form J
Slurry
n-octane
110
3
Amorphous


Form D
Slurry
n-octane/
80
3
Form E




EtOH







36:1





Form D
Slurry
water
80
1
Analyzed 







by FT-







Raman


Form A
Slurry
Cyclohexane/
Room temp.
2
Form D




EtOH







 4:1





Form A
Slurry
Acetone
Room temp.
2
Form G


Form A
Slurry
Water
Room temp.
1
Analyzed 







by FT-







Raman


Form D
Slurry
n-octane/
80
3
Analyzed 




EtOH 36:1


by FT-







Raman


Form D
Slurry
n-octane/
80
3
Analyzed 




EtOH 18:1


by FT-







Raman
















TABLE 4







Precipitation results











Starting

Temperature
Time stirred
Outcome/


material
Solvent1
(° C.)
(hours)
remarks





Form A
Cyclohexane/
70
2
Form B



EtOH 1:1; 1x






cyclohexane





Form A
n-octane/EtOH
75
1
Form D



4:1; 1x n-octane





1First solvent or solvent mixture: solvent; second solvent: antisolvent. “1x” for example means that the compound is precipitated by adding the same volume of antisolvent to the solution.






For the drying/water vapor adsorption experiments, Form D is dried under nitrogen for three days to result in Form E.







TABLE 5a







Drying/water vapor adsorption












Starting



Time 
Outcome/


material
Process
Solvent
Condition 
(days)
remarks















Form D
Water vapor
N/A
81% RH;
17
Analyzed by



adsorption

nitrogen

FT-Raman


Form G
Water vapor
N/A
81% RH;
25
Analyzed by



adsorption

nitrogen

FT-Raman


Form A
Water vapor
N/A
81% RH;
38
Analyzed by



adsorption

nitrogen

FT-Raman;







4% water and







2% ethyl







acetate


Form D
Drying
N/A
nitrogen
3
Form E


Form G
Drying
N/A
nitrogen
2
Analyzed by







FT-Raman


Form G
Drying
N/A
vacuum
34
Analyzed by







FT-Raman
















TABLE 5b







Evaporation results












Starting



Time 
Outcome/


material
Process
Solvent
Condition
(days)
remarks





Form A
Evaporation 
EtOH/
Nitrogen, 
 5
Analyzed by




water
room

FT-Raman;




19:1
temp.

crystallized







after storage in







refrigerator for







20 days


Form A
Evaporation
 0.1M 
Nitrogen, 
12
Form C,




TRIS- 
room

evaporation to




buffer
temp.

40% of initial







volume


Form A
Evaporation
0.05M 
Nitrogen, 
16
Form K,




TRIS-
room

evaporation to




buffer,
temp.

15% of initial




pH 7.4


volume









Example 1
Preparation of Colchicine Form B
311 milligrams (mg) of colchicine Form A is dissolved in 9 milliliters (ml) 1:9 (v:v) EtOH/cyclohexane at 70° C. An additional 9 ml of cyclohexane is added and the suspension is stirred for 1 hour at 70° C. The resulting solids (88 mg) are filtered, air-dried and analyzed by FT-Raman, XRPD, and TG-FTIR. FIG. 3 illustrates an XRPD pattern of Form B with a peak listing provided in Table 6 below. FIG. 4 illustrates a FT-Raman spectrum and a peak listing is provided in Table 6. The results indicate Form B is a cyclohexane solvate containing 5.6% solvent.







TABLE 6







XRPD and FT-Raman peak 


table of colchicine Form B








XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












4.28
5
3015


5.79
16
2995


9.83
8
2965


10.50
51
2936


11.68
12
2848


12.33
17
1594


12.48
25
1571


12.91
10
1553


14.03
17
1503


14.73
36
1460


16.38
36
1432


16.93
20
1416


17.47
100
1380


18.36
32
1371


19.08
31
1350


19.33
41
1323


19.78
52
1286


20.25
29
—


21.27
45
—


22.57
38
—


22.96
18
—


23.86
91
—


24.37
32
—


24.75
22
—


25.11
56
—


25.46
22
—


26.19
27
—


28.27
24
—


28.65
15
—


29.78
26
—


31.20
16
—


32.50
17
—









TG-FTIR analysis reveals a stepwise weight loss of 5.6% cyclohexane, which is strongest at about 170° C. This is typical for a solvate (4:1 colchicine to solvent 5.0%; 3:1 colchicine to solvent 6.6%). Decomposition is observed above 225° C.









TABLE 7





Temperature 
Mass loss
Released 


range
(%)
compound/comment







 25-225° C.
 5.63
cyclohexane


225-350° C.
14.28
Decomposition









Example 2
Preparation of Colchicine Form C
A. 518 mg of colchicine Form A is suspended in 0.5 ml water and stirred at room temperature. After one day a very viscous suspension is formed. An additional ml of water is added and the suspension is stirred at room temperature for 1 day. The material is stored at room temperature and 75% relative humidity (RH) for three weeks. The resulting solids are analyzed by FT-Raman, XRPD, TG-FTIR, and DVS. FIG. 5 illustrates an XRPD pattern of Form C with a peak listing provided in Table 8 below. FIG. 6 illustrates a FT-Raman spectrum and a peak listing is provided in Table 8. The results indicate Form C is a hydrate containing 7.6% water.
B. 1.9 grams (g) colchicine Form A is suspended in 5 ml water and seeded with the material from Example 2A. The suspension is stirred at room temperature for a day, filtered and dried at ambient conditions. The resulting solids are analyzed by FT-Raman and differential scanning calorimetry (DSC).







TABLE 8







XRPD and FT-Raman peak


table of colchicine Form C








XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%] 
(cm−1)












7.19
7
3041


10.11
80
3019


10.95
18
3000


11.69
36
2981


12.76
10
2930


13.35
100
2865


13.93
16
2846


14.32
23
1597


15.23
27
1587


15.55
40
1565


15.97
18
1544


16.61
59
1500


17.58
67
1434


17.93
62
1366


18.34
56
1350


18.66
31
1323


19.44
75
1285


20.30
25
1254


21.00
72
—


21.42
60
—


22.18
28
—


22.74
45
—


23.46
39
—


24.23
74
—


24.48
43
—


24.91
52
—


25.96
66
—


26.87
44
—


27.38
64
—


27.57
51
—


28.05
59
—


28.87
70
—


30.88
33
—


31.66
27
—


32.43
41
—


33.47
21
—


34.55
23
—









TG-FTIR analysis reveals a stepwise weight loss of 7.6% water, which is strongest at about 140° C. This is typical for a hydrate (sesquihydrate 6.3%). Decomposition is observed above 220° C.









TABLE 9





Temperature 
Mass loss 
Released 


range
(%)
compound/comment







 25-220° C.
 7.58
water


220-350° C.
19.25
Decomposition









Form C has a melting peak of 115° C. by DSC analysis. DVS analysis results are provided in FIGS. 7A and 7B. A standard scanning rate of 5% RH change per hour is used in the measurement. Below 10% RH a strong loss of water is observed. At 0% RH the sample likely contains no water. Above a few % RH a strong and stepwise water uptake is observed suggesting the product at 0% RH is highly hygroscopic. The plateau observed at about 7.5% RH may suggest the presence of another hydrate
Example 3
Preparation of Colchicine Form D
A. A solubility study is run to determine the solubility of colchicine Form A in 1:1 (v:v) cyclohexane/ethanol at room temperature. After 1 day at room temperature, a precipitate is observed and isolated. 461 mg of colchicine Form A is suspended in 2.0 ml 4:1 (v/v) cyclohexane/ethanol and stirred at room temperature for 1 day. The suspension is seeded with the precipitate from the solubility study and stirred 1 day at room temperature, filtered, and air dried for about 3 minutes at room temperature (293 mg). The resulting solids are analyzed by FT-Raman, and TG-FTIR. The results indicate Form D is an ethanol solvate containing about 10.2% ethanol.
B. Suspended 1.02 g of colchicine in 4 ml 4:1 (v/v) cyclohexane/ethanol, seed with material from Example 3A and stirred for 1 day at room temperature. The resulting material is filtered and dried under ambient conditions; the resulting solid is analyzed by FT-Raman and XRPD.
C. Suspended 2 g of colchicine Form A in 8 ml 4:1 (v/v) cyclohexane/ethanol, seed with material from Example 3B and stirred for 2 days at room temperature. The resulting material is filtered and dried under ambient conditions; the resulting solid is analyzed by FT-Raman, TG-FTIR, DSC, and 1H-NMR.
FIG. 8 illustrates an XRPD pattern of Form D with a peak listing provided in Table 10 below. FIG. 9 illustrates a FT-Raman spectrum and a peak listing is provided in Table 10.







TABLE 10







XRPD and FT-Raman peak 


table of colchicine Form D








XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












9.45
31
3027


9.75
6
3016


10.88
24
2968


11.21
7
2933


12.44
20
2840


12.97
16
1588


13.63
37
1569


14.91
20
1549


15.46
16
1501


16.26
70
1443


17.29
10
1436


18.31
45
1399


18.76
57
1352


19.66
13
1325


20.62
23
1283


21.16
100
1269


22.25
20
—


22.58
25
—


23.62
12
—


24.32
36
—


24.65
31
—


25.10
49
—


25.78
28
—


26.45
31
—


26.65
23
—


27.26
22
—


28.14
30
—


28.48
12
—


30.10
14
—


30.91
16
—


31.77
14
—


32.50
14
—


33.02
13
—


33.52
18
—









TG-FTIR analysis reveals a stepwise weight loss of 10.2% ethanol, which is strongest at about 130° C. This is typical for a solvate (monosolvate 10.3%). Decomposition is observed above 270° C.









TABLE 11





Temperature 
Mass loss 
Released 


range
(%)
compound/comment







 25-270° C.
10.16
ethanol


270-350° C.
17.65
Decomposition









Under DSC analysis, a melting peak with a shoulder is observed at 95° C. and a weak endothermic event at 62° C. Under 1H-NMR analysis in CDCl3 0.9 mol equivalent of ethanol is observed.
Example 4
Preparation of Colchicine Form E
A. 280 mg of colchicine Form D obtained according to Example 3B is suspended in 3.0 ml 36:1 (v/v) n-octane/ethanol. The mixture is slowly heated to 80° C. to form a slightly yellow suspension that is stirred at 80° C. for 2 days. The suspension is hot filtered and dried under nitrogen for 1 day at room temperature. The resulting solids are analyzed by FT-Raman, XRPD, and TG-FTIR. FIG. 10 illustrates an XRPD pattern of Form E with a peak listing provided in Table 12 below. FIG. 11 illustrates a FT-Raman spectrum and a peak listing is provided in Table 12. The results indicate Form E is likely an ansolvate containing about 2.1% n-octane or 2.3% water depending upon preparation.







TABLE 12







XRPD and FT-Raman peak 


table of colchicine Form E








XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












6.61
4
2984


8.16
12
2933


9.79
75
2836


11.76
41
1577


13.13
48
1503


13.81
81
1459


15.60
43
1429


16.16
50
1413


17.79
42
1350


19.64
52
1324


20.36
100
1280


20.88
41
1249


22.00
55
—


22.59
49
—


23.67
45
—


24.75
57
—


25.71
31
—


26.90
73
—


28.00
38
—


28.89
20
—


29.72
22
—









TG-FTIR analysis reveals about 2% loosely bound solvent indicating Form E is likely an ansolvate. The solvent is likely residual solvent from synthesis. Decomposition is observed above 250° C.









TABLE 13





Temperature 
Mass loss 
Released 


range
(%)
compound/comment







 25-250° C.
2.12
n-octane


250-350° C.
9.77
Decomposition









B. 301 mg of colchicine Form D obtained according to Example 3C is dried under nitrogen for 3 days at room temperature. The resulting material is analyzed by FT-Raman, XRPD, and TG-FTIR.
TG-FTIR analysis reveals about 2% loosely bound solvent indicating Form E is likely an ansolvate. The solvent is likely residual solvent from synthesis and water may be due to open handling of the sample. Decomposition is observed above 250° C.









TABLE 14





Temperature range
Mass loss (%)
Released compound/comment







 25-250° C.
2.28
Water; small amt cyclohexane


250-350° C.
9.60
Decomposition









Example 5
Preparation of Colchicine Form F, Non-Crystalline
1.9 grams of Form A is suspended in 5 ml water, seeded, stirred for 1 day at room temperature and isolated. 485 mg of the isolated material is dried under nitrogen for 3 days at room temperature and then heated under nitrogen to 160° C. for minutes. The non-crystalline material is cooled to room temperature in ten minutes (“melt quenching”). The material is analyzed by FT-Raman, XRPD, TG-FTIR and DSC indicating an amorphous form. FIG. 12 illustrates an XRPD pattern of Form F. FIG. 13 illustrates a FT-Raman spectrum and a peak listing is provided in Table 15.







TABLE 15





FT-Raman peak table of colchicine Form F


FT-Raman peaks (cm−1)







2934


2841


1586


1504


1430


1351


1323


1285









TG-FTIR analysis reveals about 1.2% loosely water indicating it is likely derived from open handling of the sample suggesting the Form F is hygroscopic. Decomposition is observed above 280° C.









TABLE 16





Temperature range
Mass loss (%)
Released compound/comment







 25-180° C.
1.21
Water


180-350° C.
8.60
Decomposition









Analysis by DSC indicates in a first scan, a pronounced Tg at 98° C. and an event at 28° C. which possibly corresponds to a Tg as well. The water observed in TG-FTIR may lower the Tg at the surface of the sample leading to the observation of the Tg at 28° C. An endothermic event is observed at 129° C. possibly corresponding to a melting of a minor crystalline phase. An event observed at 157° C. is thought to be an artifact. A second scan is taken on the same sample after a fast cooling to −50° C. A Tg is observed at 98° C. The absence of other events in the second scan indicates the sample is completely amorphous and homogenous after melting and fast cooling.
Example 5
Preparation of Colchicine Form G
A. 500 mg of colchicine Form A is suspended in 1.0 ml acetone and stirred for 1 day at room temperature to form a very viscous suspension. An additional 0.8 ml acetone is added and the suspension is stirred at room temperature for 1 day, filtered and dried at room temperature for 2.5 hours under nitrogen (150 mg). The material is analyzed by FT-Raman and TG-FTIR indicating an acetone solvate containing 18.3% solvent, an amount which may strongly depend upon sample preparation.
B. 2.1 g of colchicine Form A is suspended in 9.0 ml acetone, seeded with material from Example 5A and stirred at room temperature for 2 days. The resulting solid is filtered and dried under ambient conditions. The material is analyzed by FT-Raman, XRPD, DSC, and 1H-NMR.
FIG. 14 illustrates an XRPD pattern of Form G with a peak listing provided in Table 17 below. FIG. 15 illustrates a FT-Raman spectrum and a peak listing is provided in Table 17.







TABLE 17







XRPD and FT-Raman peak table of colchicine Form G










XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












9.39
18
3032


10.09
5
2998


10.83
5
2963


11.71
9
2935


12.01
20
2839


12.41
26
1708


13.34
5
1669


14.64
16
1596


15.12
7
1559


15.56
7
1504


16.44
52
1460


17.58
11
1431


18.87
100
1400


19.67
35
1366


20.03
24
1347


20.94
53
1323


21.80
18
1292


22.28
27
—


22.66
12
—


23.82
27
—


24.44
21
—


25.01
23
—


25.59
32
—


26.68
19
—


27.55
14
—


28.06
19
—


29.01
18
—


29.63
13
—


30.37
12
—


30.92
13
—


31.27
11
—


32.48
15
—


32.87
10
—


33.26
11
—


34.60
9
—









TG-FTIR analysis reveals a stepwise loss of 18.3% acetone which is strongest around 110° C. The results are typical of a solvate (monosolvate 12.7%; disolvate 22.5%) Decomposition is observed above 200° C.









TABLE 18





Temperature range
Mass loss (%)
Released compound/comment







 25-200° C.
18.32
acetone


200-350° C.
11.13
Decomposition









TG-FTIR on a completely dry sample shows a solvent content of 8.1%, but the Raman spectrum of the completely dry sample is different from the fresh sample indicating solvent content may vary with sample preparation.
DSC analysis indicates Form G has a melting peak of 87° C. 1H-NMR analysis indicates 0.7 mol equivalent of acetone.
Example 6
Preparation of Colchicine Form H
A solubility study is run to determine the solubility of colchicine Form A in 1,4-dioxane at room temperature. After 1 day at room temperature, a precipitate is observed and isolated. 471 mg of colchicine Form A is suspended in 1.0 ml 1,4-dioxane and seeded with the precipitate from the solubility study. The suspension is stirred for 2 days at room temperature, filtered, and dried under ambient conditions for several minutes (296 mg). The material is analyzed by FT-Raman, XRPD, and TG-FTIR. FIG. 16 illustrates an XRPD pattern of Form H with a peak listing provided in Table 19 below. FIG. 17 illustrates a FT-Raman spectrum and a peak listing is provided in Table 19. The analysis indicates the material is a dioxane solvate containing about 15.6% solvent.







TABLE 19







XRPD and FT-Raman peak table of colchicine Form H










XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












9.41
8
2966


10.50
5
2940


11.10
13
2846


12.04
25
1573


13.32
37
1503


14.57
38
1442


15.36
27
1430


15.78
100
1400


17.04
34
1353


18.05
65
1324


18.25
64
1283


18.92
18
—


19.81
37
—


20.03
44
—


20.35
72
—


20.59
71
—


22.00
63
—


22.33
34
—


22.78
23
—


23.64
39
—


24.13
42
—


24.35
58
—


25.50
20
—


25.95
34
—


26.53
31
—


27.22
18
—


27.56
28
—


28.63
18
—


29.15
16
—


29.48
18
—


30.77
15
—


31.17
21
—


31.95
17
—


32.59
17
—


34.11
19
—


34.48
17
—









TG-FTIR analysis reveals a stepwise weight loss of 15.6% dioxane which is strongest around 160° C. The results are typical of a solvate (monosolvate 18.1%) Decomposition is observed above 250° C.









TABLE 20





Temperature range
Mass loss (%)
Released compound/comment







 25-250° C.
15.58
dioxane


250-350° C.
14.14
Decomposition









Example 7
Preparation of Colchicine Form I
A solubility study is run to determine the solubility of colchicine Form A in tetrahydrofuran at room temperature. After several days at 4° C., a precipitate is observed and isolated. 503 mg of colchicine Form A is suspended in 1.0 ml tetrahydrofuran and seeded with the precipitate from the solubility study. The suspension is stirred for 1 day at room temperature forming a very viscous suspension. An additional 0.3 ml tetrahydrofuran is added and the suspension is stirred at room temperature for 1 day, filtered, and dried under ambient conditions for several minutes (268 mg). The material is analyzed by FT-Raman, XRPD, and TG-FTIR. FIG. 18 illustrates an XRPD pattern of Form I with a peak listing provided in Table 21 below. FIG. 19 illustrates a FT-Raman spectrum and a peak listing is provided in Table 21. The analysis indicates the material is a tetrahydrofuran solvate containing about 6.3% solvent.







TABLE 21







XRPD and FT-Raman peak table of colchicine Form I










XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












4.32
7
2967


5.84
15
2939


9.02
7
2840


9.86
16
1594


10.64
54
1569


11.74
23
1553


12.43
17
1503


12.61
18
1460


12.97
16
1433


14.10
30
1415


14.77
45
1382


15.91
18
1371


16.45
56
1350


16.95
40
1323


17.61
100
1286


18.45
39
—


19.10
56
—


19.45
51
—


19.96
61
—


20.31
53
—


21.06
31
—


21.44
56
—


21.73
32
—


22.21
21
—


22.70
51
—


23.12
31
—


23.94
69
—


24.12
77
—


24.47
58
—


25.10
61
—


25.43
51
—


26.23
48
—


27.04
27
—


27.46
25
—


27.92
31
—


28.51
25
—


28.85
26
—


29.77
28
—


30.09
31
—


31.36
23
—


32.37
26
—


32.80
22
—


33.27
18
—


33.83
19
—









TG-FTIR analysis reveals a stepwise weight loss of 6.3% tetrahydrofuran which is strongest around 170° C. The results are typical of a solvate (hemisolvate 8.3%; 3:1 colchicine to solvate 5.7%) Decomposition is observed above 270° C.









TABLE 22





Temperature range
Mass loss (%)
Released compound/comment

















 25-270° C.
6.28
THF


270-350° C.
20.13
Decomposition









Example 8
Preparation of Colchicine Form J
470 mg of colchicine Form A is suspended in 1.0 ml 3:1 (v/v) toluene/acetonitrile and stirred for 2 days at room temperature, filtered, and dried under ambient conditions for several minutes (297 mg). The material is analyzed by FT-Raman, XRPD, and TG-FTIR. FIG. 20 illustrates an XRPD pattern of Form J with a peak listing provided in Table 23 below. FIG. 21 illustrates a FT-Raman spectrum and a peak listing is provided in Table 23. The analysis indicates the material is a toluene solvate containing about 16.3% solvent.







TABLE 23







XRPD and FT-Raman peak table of colchicine Form J










XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












9.46
19
3065


10.43
15
3024


11.11
10
3002


11.66
7
2933


11.96
17
2841


13.27
43
1590


14.50
41
1574


14.97
12
1502


15.67
76
1441


17.00
44
1430


18.10
73
1400


18.98
16
1379


19.57
23
1350


19.86
39
1321


20.15
36
1283


20.43
41
1252


21.99
16
—


22.31
28
—


22.56
17
—


23.42
31
—


24.26
100
—


24.53
28
—


25.26
24
—


25.62
41
—


26.30
42
—


27.02
15
—


27.42
40
—


28.22
12
—


28.77
8
—


29.24
22
—


29.78
11
—


30.14
12
—


30.42
19
—


30.97
13
—


31.28
15
—


32.13
12
—


32.71
10
—


34.17
11
—


34.79
15
—









TG-FTIR analysis reveals a stepwise weight loss of 16.3% toluene which is strongest around 160° C. The results are typical of a solvate (monosolvate 18.7%) Decomposition is observed above 240° C.









TABLE 24





Temperature range
Mass loss (%)
Released compound/comment







 25-240° C.
16.27
toluene


240-350° C.
12.75
Decomposition









Example 9
Preparation of Colchicine Form K
599 mg of colchicine Form A is dissolved in 30 ml 0.05 M tris(hydroxymethyl)-aminomethane buffer substance pH 7.4 (Fluka, 0.05 M in water). The solution was filtered through a 0.4 micrometer nylon filter. The solvent was allowed to slowly evaporate under nitrogen to 15% of the initial volume (16 days). Large crystals are obtained and analyzed by FT-Raman, XRPD, TG-FTIR, and 1H-NMR. FIG. 22 illustrates an XRPD pattern of Form K with a peak listing provided in Table 25 below (it should be noted that it is unknown whether peaks below 5° 2-theta are present). FIG. 23 illustrates a FT-Raman spectrum and a peak listing is provided in Table 25. The analysis indicates the material is probably a hydrate containing 8.7% water.







TABLE 25







XRPD and FT-Raman peak table of colchicine Form K










XRPD peaks
FT-Raman peaks









2θ [°]
Intensity [%]
(cm−1)












6.12
2
2931


10.17
4
2866


10.32
5
1597


11.95
100
1587


13.48
11
1565


13.59
12
1544


14.11
2
1500


14.55
2
1435


15.47
3
1350


15.74
3
1323


16.15
2
1297


16.79
4
1285


17.84
86
1254


18.09
12
—


18.52
28
—


18.79
7
—


19.63
7
—


19.95
6
—


21.13
8
—


21.34
9
—


21.61
14
—


21.75
8
—


22.92
5
—


23.78
52
—


24.23
8
—


24.40
10
—


25.01
10
—


25.16
14
—


27.65
13
—


28.26
11
—


28.97
8
—


30.97
8
—









TG-FTIR analysis on a single crystal reveals a stepwise weight loss of 8.7% water which is strongest around 140° C. The results are typical of a hydrate (dihydrate 8.3%) Decomposition is observed above 250° C.









TABLE 26





Temperature range
Mass loss (%)
Released compound/comment

















 25-250° C.
8.71
water


250-350° C.
15.46
Decomposition









1H-NMR analysis in CDCl3 indicates no peak for tris(hydroxymethyl-aminomethane around 3.2 ppm. However, three additional signals at around 1.6, 1.2, and 0.8 ppm are present for a total of 11 protons indicating the sample contains a substantial amount of another organic compound.
Example 10
Preparation of Colchicine Form L
1.08 g of Form A is suspended in 4 ml 4:1 (v/v) cyclohexane/EtOH, seeded, and stirred at room temperature for 1 day. The resulting material is filtered and shortly dried at ambient conditions. 300 mg of the material is suspended in 3 ml mesitylene and heated to 70° C. to form a yellow gel. The gel is sonicated for 15 minutes at room temperature. The temperature is cycled between 40 and 80° C. for 1 day. The white suspension is heated to 110° C. and dissolved. The resulting material is sonicated for 15 minutes at room temperature and the temperature is cycled between and 80° C. for 1 day. The white material is filtered at 80° C. and dried under nitrogen. The resulting material is analyzed by FT-Raman and TG-FTIR. FIG. 24 illustrates FT-Raman spectrum of colchicine mesitylene solvate with a peak listing provided in Table 27 below. The analysis indicates the material is likely a mesitylene solvate.







TABLE 27





FT-Raman peak table of colchicine Form L


FT-Raman peaks (cm−1)







2999


2935


2840


1591


1570


1553


1503


1459


1432


1415


1382


1349


1323


1286









TG-FTIR analysis reveals two stepwise weight losses of a total of 9% mesitylene, which are strongest around 140° C. and 230° C. The results with the second step suggest at least part of the solvent is bound and the material is probably a solvate (6:1 solvate of colchicine to solvent 4.8%; 3:1 solvate of colchicine to solvent 9.1%) Decomposition is observed above 280° C.









TABLE 28





Temperature range
Mass loss (%)
Released compound/comment







 25-160° C.
4.06
mesitylene


160-280° C.
4.89
mesitylene


280-350° C.
8.84
Decomposition









The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”). The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or”. The endpoints of all ranges directed to the same component or property are inclusive and independently combinable.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
Embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

## Claims

1. A method of treating acute gouty arthritis and pain in attacks of acute gouty arthritis, cystic fibrosis, demyelinating diseases of central or peripheral origin, multiple sclerosis, Dupuytren's contracture, idiopathic pulmonary fibrosis, primary amyloidosis, recurrent pericarditis, acute pericarditis, asthma, postpericardiotomy syndrome, Behçet's disease, Familial Mediterranean fever, idiopathic thrombocytopenic purpura, primary biliary cirrhosis, or pyoderma gangrenosum, or prevention of attacks of acute gouty arthritis and pain in attacks of acute gouty arthritis, or chronic gout prophylaxis in a patient, comprising:
administering to the patient in need thereof a therapeutically effective amount of a colchicine solid state form;
wherein the colchicine solid state form comprises
a. Colchicine Form B cyclohexane solvate comprising XRPD peak positions at 5.79, 10.50, 17.47, and 23.86±0.2 degrees 2-theta;
b. Colchicine Form D ethanol solvate comprising XRPD peak positions at 9.45, 16.26, and 21.16±0.2 degrees 2-theta;
c. Colchicine Form G acetone solvate comprising XRPD peak positions at 9.39, 16.44, and 18.87±0.2 degrees 2-theta;
d. Colchicine Form H dioxane solvate comprising XRPD peak positions at 12.04, 15.78, 18.05, and 18.25±0.2 degrees 2-theta;
e. Colchicine Form I tetrahydrofuran solvate comprising XRPD peak positions at 5.84, 10.64, and 17.61±0.2 degrees 2-theta;
f. Colchicine Form J toluene solvate comprising XRPD peak positions at 9.46, 15.67, 18.10, and 24.26±0.2 degrees 2-theta; or
g. Colchicine Form L mesitylene solvate comprising Raman peaks at 2935 and 1503±2 cm−1.

2. The method of claim 1, wherein Colchicine Form B cyclohexane solvate comprises XRPD peak positions at 5.79, 10.50, 17.47, and 23.86±0.2 degrees 2-theta.

3. The method of claim 1, wherein Colchicine Form B cyclohexane solvate comprises one or more of the following:
XRPD peak positions at 5.79, 10.50, 17.47, 19.78, 23.86, and 25.11±0.2 degrees 2-theta; or
Raman peaks at 2936, 1594, 1571, 1553, and 1503±2 cm-1.

4. The method of claim 1, wherein Colchicine Form D ethanol solvate comprises XRPD peak positions at 9.45, 16.26, and 21.16±0.2 degrees 2-theta.

5. The method of claim 1, wherein Colchicine Form D ethanol solvate comprises one or more of the following:
XRPD peak positions at 9.45, 16.26, 18.31, 18.76, 21.16, and 25.10±0.2 degrees 2-theta;
Raman peaks at 2933, 1549, 1501, and 1436±2 cm-1; or
a melting peak of about 95° C. by DSC analysis.

6. The method of claim 1, wherein Colchicine Form G acetone solvate comprises XRPD peak positions at 9.39, 16.44, and 18.87±0.2 degrees 2-theta.

7. The method of claim 1, wherein Colchicine Form G acetone solvate comprises one or more of the following:
XRPD peak positions at 9.39, 12.41, 16.44, 18.87, and 20.94±0.2 degrees 2-theta;
Raman peaks at 2935, 1596, 1559, 1504, and 1431±2 cm-1; or
a melting peak of about 87° C. by DSC analysis.

8. The method of claim 1, wherein Colchicine Form H dioxane solvate comprises XRPD peak positions at 12.04, 15.78, 18.05, and 18.25±0.2 degrees 2-theta.

9. The method of claim 1, wherein Colchicine Form H dioxane solvate comprises one or more of the following:
XRPD peak positions at 12.04, 15.78, 18.05, 18.25, 20.35, and 20.59, ±0.2 degrees 2-theta; or
Raman peaks at 2940, 1573, and 1503±2 cm-1.

10. The method of claim 1, wherein Colchicine Form I tetrahydrofuran solvate comprises XRPD peak positions at 5.84, 10.64, and 17.61±0.2 degrees 2-theta.

11. The method of claim 1, wherein Colchicine Form I tetrahydrofuran solvate comprises one or more of the following:
XRPD peak positions at 5.84, 10.64, 16.45, 17.61, 23.94, and 24.12±0.2 degrees 2-theta; or
Raman peaks at 2939, 1594, 1569, 1553, and 1503±2 cm-1.

12. The method of claim 1, wherein Colchicine Form J toluene solvate comprises XRPD peak positions at 9.46, 15.67, 18.10, and 24.26±0.2 degrees 2-theta.

13. The method of claim 1, wherein Colchicine Form J toluene solvate comprises one or more of the following:
XRPD peak positions at 9.46, 13.27, 14.50, 15.67, 17.00, 18.10, and 24.26±0.2 degrees 2-theta; or
Raman peaks at 2933, 1590, 1574, and 1502±2 cm-1.

14. The method of claim 1, wherein Colchicine Form L mesitylene solvate comprises Raman peaks at 2935 and 1503±2 cm−1.

15. The method of claim 1, wherein Colchicine Form L mesitylene solvate comprises Raman peaks at 2935, 1591, 1570, 1553, and 1503±2 cm-1.

16. The method of claim 1, wherein the colchicine solid state form is formulated into a dosage form further comprising a pharmaceutically acceptable excipient.