CN1964966A - Rosiglitazone phosphate and polymorphic forms - Google Patents

Abstract

This invention relates to 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, a novel salt of rosiglitazone, and to novel polymorphs thereof. The invention also relates to methods for preparing rosiglitazone phosphate and its polymorphs. The compounds of this invention are intended for the treatment and/or prevention of diabetes, diabetes-related conditions, and some of their complications.

Description

Rosiglitazone Phosphate and Polymorphs

field of invention

The present invention relates to novel compounds, to processes for the preparation of the compounds, to pharmaceutical compositions comprising the compounds, and to the use of the compounds and the compositions in medicine. Furthermore, the present invention encompasses different polymorphic forms of the novel compounds.

Background of the invention

European Patent Application Publication No. 0306228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycemic and hypolipidemic activity. The compound of EP-A-0306228 embodiment 30 is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione ( According to Merck Index/13th Edition, Topic No. 8346, CAS Registry No.: 122320-73-4), ie rosiglitazone.

International application publication number WO 94/05659 discloses certain salts of the compounds of EP-A-0306228. The preferred WO 94/05659 salt is the maleate.

There remains a need for alternative salt forms that are directly prepared and have properties suitable for pharmaceutical processing on a commercial level.

Description of the invention

The present inventors have prepared and described the phosphate salt of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, That is, 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, hereinafter also referred to as "phosphate "), and this "phosphate" has been found to be particularly stable and thus suitable for large-scale preparation and handling.

Furthermore, the present inventors have prepared and described different polymorphs of said "phosphate", namely polymorphs A, B, B1, C, D and E. Polymorphism is generally defined as the ability of a substance, such as a pharmaceutically active substance, to possess two or more different crystal structures. The different crystal forms are respectively called polymorphs. The substances may also enclose solvent molecules during crystallization, and these solvates or hydrates are called pseudopolymorphs. The different polymorphs, pseudopolymorphs, or amorphous forms of a given substance have different properties in one or more parameters such as melting point, solubility and dissociation, true density, crystal shape, compaction characteristics, flow properties, and/or solid-state stability. Physical properties are not the same as each other. They are expected to affect pharmaceutical properties such as dissolution rate and/or bioavailability. It is also economically desirable for certain substances to be stable for longer periods of time without requiring special storage conditions. Therefore, it is important to evaluate polymorphic forms of pharmaceutically active substances. The term "polymorph" as used herein is understood to include both polymorphic and pseudopolymorphic forms of the compound of the invention, ie, the phosphate salt. Furthermore, "polymorphic form", "crystal form", "polymorph", "crystalline polymorph" and "crystalline polymorphic form" as used herein are understood to have the same meaning and are interchangeable .

5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione as used herein is understood to mean rosiglitazone in free base form .

The novel phosphate salts and their polymorphs also have useful pharmaceutical properties and can be used to treat and/or prevent diabetes, diabetes-related disorders and some of its complications.

Accordingly, in one aspect, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and phosphoric acid salts, or solvated or unsolvated forms thereof.

In a further aspect, the present invention provides novel phosphoric acids of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Novel polymorphs of salts, which are referred to herein as Forms A, B, B1, C, D or E, and which may be in the form of solvates (forms A, C and D), such as hydrated forms (forms A and C) or solvates with methanol (form D); or unsolvated forms, such as anhydrous forms (forms B, B1 and E ).

The term "unsolvated form" as used herein is understood to mean substantially free of residual inorganic or organic solvent medium, for example in anhydrous form.

Since phosphoric acid is a tribasic acid, there is theoretically more than one stoichiometry of phosphate. But so far, the inventors have only isolated 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and The molar ratio of phosphoric acid is or is about 1:1 of the phosphate salt, wherein said molar ratio comprises a molar ratio of 1:0.9 to 1:1.2. In theory, the molar ratio of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione to phosphoric acid can also be 3:1 or 2:1. The present invention also encompasses these molar ratios.

Accordingly, in a further aspect, the present invention provides the phosphoric acid of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione A salt, or a solvate or non-solvate form thereof, wherein 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazole The molar ratio of alkanedione to phosphate is 1:1.

In addition, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate or its solvate or unsolvated form, and its polymorphs A, B, B1, C, D and E, wherein 5-[[4-[2-(methyl-2-pyridylamino)ethoxy The molar ratio of ]phenyl]methyl]-2,4-thiazolidinedione to phosphate is 1:1. In the following, where the molar ratio of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione to phosphate is 1 : 1 of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate is also known as "5-[ [4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate (1:1)".

Preferably, "phosphate" is hydrated or non-hydrated. More preferably, "phosphate" is in its polymorphic form A, B, B1 or E.

The phosphate salts and polymorphs thereof may exist in one of several tautomeric forms, all tautomeric forms being encompassed by the present invention. It is understood that the present invention encompasses all isomeric forms of phosphate salts, preferably hydrates, including any stereoisomeric forms thereof, whether individual isomers or mixtures of isomers.

Without wishing to be bound by any particular mechanism or theory, applicants believe that in the 1:1 salt, the phosphate anion in addition to binding 5-[[4-[2-(methyl-2-pyridylamino)ethoxy] In addition to phenyl]methyl]-2,4-thiazolidinedione, protons (hydrogen atoms) can also be bound, or other cations, for example alkali metal cations or ammonium cations, can be bound. In this case, the salt can be described as a mixed salt.

As mentioned above, a preferred aspect of the present invention is a hydrate or non-hydrate of a phosphate salt, wherein said hydrate or non-hydrate of a phosphate salt is also referred to hereinafter as "phosphate hydrate" or "phosphate non-hydrate, respectively. thing". The phosphate hydrate exists in polymorphic form A or C, with form A being preferred, whereas the phosphate anhydrate exists in polymorphic form B, B1 or E; depending on the preparation described below method and/or the corresponding raw materials used.

Accordingly, in one aspect, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate in water A crystalline polymorph in the form of a compound, wherein 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and phosphate in a molar ratio of 1:1, referred to herein as Form A, which is characterized by an X-ray powder diffraction (XRPD) pattern at values in degrees 2-theta of approximately 15.63, 15.75, 17.30, 19.61, and 21.47 has an intensity peak. Crystalline polymorph A may also exhibit an intensity peak at any one or more of the following values expressed in degrees 2-theta: about 4.28, 5.38, 8.61, 9.92, 12.44, 14.04, 16.91, 21.66, 22.54, 24.10, 24.43, 24.77, 25.06, 25.81 and 26.28.

In another aspect, crystalline polymorph Form A is characterized by an X-ray powder diffraction (XRPD) pattern substantially consistent with Table 1 and Figure 1 .

Table 1: X-ray powder diffraction (XRPD) pattern of Form A, showing interplanar spacing (d, unit _, ie: Angstrom), characteristic XRPD angle (2θ°) and relative intensity (%)

d-value (_) Angle 2θ° Relative Strength(%) 22.66 3.90 13 20.63 4.28 twenty one 16.42 5.38 18 14.20 6.22 7 10.51 8.41 16 10.26 8.61 19 9.879 8.94 7 8.911 9.92 18 8.170 10.82 6 7.514 11.77 7 7.111 12.44 twenty four 6.828 12.96 10 6.748 13.11 9 6.497 13.62 13 6.301 14.04 31 5.667 15.63 65 5.622 15.75 100 5.514 16.06 16 5.239 16.91 19 5.123 17.30 42 4.924 18.00 17 4.855 18.26 9

4.663 19.02 15 4.524 19.61 35 4.342 20.44 14 4.135 21.47 40 4.100 21.66 33 4.037 22.00 16 3.941 22.54 30 3.876 22.93 12 3.817 23.29 13 3.803 23.37 15 3.777 23.54 16 3.741 23.77 15 3.690 24.10 18 3.641 24.43 18 3.591 24.77 18 3.550 25.06 18 3.449 25.81 19 3.389 26.28 twenty three 3.279 27.17 8 3.227 27.62 14 3.201 27.85 14 3.128 28.51 9 3.066 29.11 10 3.025 29.51 14 2.957 30.20 9 2.922 30.57 12 2.910 30.70 13 2.829 31.60 10 2.807 31.86 9 2.774 32.25 9 2.759 32.42 9 2.711 33.01 7 2.674 33.49 7 2.617 34.24 10 2.608 34.36 11 2.568 34.91 8 2.556 35.08 8 2.452 36.61 7 2.421 37.11 7 2.367 37.98 6 2.330 38.60 7 2.302 39.10 8 2.273 39.62 8

Optionally, crystalline polymorph A is additionally characterized by infrared spectroscopy as shown in FIG. , 1110, 1028, 928, 821, 767, 716 cm ^-1 observed spectral bands. Thus, Form A provided an infrared spectrum substantially consistent with that of FIG. 2 .

The infrared absorption spectra of the polymorphs of the phosphate salts described herein were measured using a BRUKERFT IR-Tensor 27.

As described below, the X-ray powder diffraction (XRPD) patterns presented herein were obtained using an X-ray powder diffractometer D-8 (AXS-BRUKER) and copper radiation with a 2-theta accuracy of ±0.05 degrees for the sample data. ) to measure:

According to the Kofler method (eg as described in Vogel, A.I., Practical Organic Chemistry, 3rd edition, p. 82), Form A has a melting point in the range of 171-177°C.

Thus, Form A is the ratio of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione to phosphoric acid (molar ratio ) is a 1:1 phosphate and is isolated as a phosphate hydrate comprising water in a weight ratio of about 0.1%-4.5%, eg about 0.8%-4%, eg preferably 1.6%-3.6%.

A specific example of Form A contains about 0.87% water, corresponding to a 1:0.23 hydrate. More specific examples comprise about 1.6% water, corresponding to a 1:0.42 hydrate; or about 2.3% water, corresponding to a 1:0.60 hydrate; or about 3.3% water, corresponding to a 1:0.79 hydrate hydrate; or contain 3.58% water, equivalent to 1:0.94 hydrate. All percentages are by weight.

Drying Form A at, for example, room temperature yields a hydrate of about 1:0.4; assisted drying with a strong desiccant such as _P2O5 at about 45°C yields a hydrate of about 1:0.3 _; High temperatures, preferably 80° C., optionally with further drying, can result in water contents below 0.1% by weight. Room temperature as used herein is understood to mean an average temperature of from about 20°C to about 35°C, for example from about 25°C to about 28°C.

Exposure of Form A to high humidity produces an approximately 1:1 hydrate.

Accordingly, 5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate salt of Form A ( The crystalline polymorph in the form of a 1:1) hydrate contains about not more than 4.5% water by weight, such as containing about 3.6% water by weight, corresponding to a hydrate of 1:0.94, or such as containing about 1.6% The weight ratio of water is equivalent to 1:0.42 hydrate.

In another aspect, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate A crystalline polymorph in the form of a substance, wherein 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and Phosphate salt in a 1:1 molar ratio, referred to herein as Form C, is characterized by an X-ray powder diffraction (XRPD) pattern at values of approximately 12.86, 15.98, 16.26, 21.60, and 24.50 in degrees 2-theta have intensity peaks. Crystalline polymorph C may also exhibit an intensity peak at any one or more values selected from the group consisting of about 11.32, 14.50, 16.47, 18.91, 19.99, 20.30, 23.45, 24.34, and 29.40 in degrees 2-theta.

The water content of the crystal form C is in the range of 3.8-3.9% by weight.

On the other hand, the X-ray powder diffraction (XRPD) pattern characteristics of crystalline polymorph C are substantially consistent with Table 2 and FIG. 3 .

Table 2: X-ray powder diffraction (XRPD) pattern of Form C, showing interplanar spacing (d, unit _, ie: Angstrom), characteristic XRPD angle (2θ°) and relative intensity (%)

d-value (_) Angle 2θ° Relative Strength(%) 22.18 3.98 20 10.93 8.08 5 8.842 10.00 4 7.809 11.32 38 7.294 12.12 20 6.876 12.86 62 6.104 14.50 25 5.542 15.98 100 5.448 16.26 79 5.377 16.47 57 5.193 17.06 7 4.945 17.92 13 4.911 18.05 11 4.689 18.91 45 4.438 19.99 55 4.371 20.30 30 4.250 20.89 17 4.112 21.60 59 4.072 21.81 twenty one 3.961 22.43 twenty two

3.887 22.86 16 3.791 23.45 55 3.654 24.34 57 3.631 24.50 64 3.552 25.05 20 3.456 25.76 17 3.400 26.19 12 3.278 27.18 13 3.179 28.04 twenty four 3.139 28.41 17 3.122 28.57 15 3.036 29.40 26 3.005 29.71 16 2.963 30.14 14 2.893 30.88 8 2.814 31.78 17 2.775 32.24 5 2.685 33.35 16 2.610 34.34 7 2.578 34.77 11 2.470 36.34 3 2.426 37.02 4 2.329 38.62 9

Optionally, crystalline polymorph C is additionally characterized by infrared spectroscopy as shown in FIG. , 1541, 1513, 1464, 1443, 1416, 1392, 1363, 1332, 1301, 1265, 1249, 1218, 1179, 1163, 1113, 1096, 1048, 1028, 995, 951, 926, 905, 823, 812, 774 , 739, 713cm ^-1 observed spectral bands. Thus, Form C provided an infrared spectrum substantially consistent with that of FIG. 4 .

The invention also encompasses the phosphate salts in unsolvated form, for example polymorphs B, B1 or E. The crystalline form may be anhydrous, i.e. may be a non-hydrate, which may contain less than 2% by weight of water, such as not more than 1.5%, such as crystal forms B and B1, or such as not more than 0.5%, such as not More than 0.2%, eg less than 0.1% by weight of water, such as Form E. The presence of traces of water in the above polymorphs B, B1 or E is dependent on the presence of humidity, i.e. high relative humidity (e.g. about 80% or higher) leads to a higher water content in the above polymorphs, Whereas low relative humidity (eg not more than 30%) results in lower water content of the aforementioned polymorphs. Preferably, the non-hydrated hydrate described above substantially leaves no organic solvent medium.

Accordingly, in a further aspect, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate A crystalline polymorph of a salt in which 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and phosphoric acid The salt has a molar ratio of 1:1, referred to herein as Form B, and its X-ray powder diffraction (XRPD) pattern is characterized by the presence of intensity peak. Crystalline polymorph B may also exhibit an intensity peak at any one or more of the values in degrees 2-theta selected from the group consisting of about 8.44, 19.50, 20.86, 22.15, 25.67, 26.22, and 27.70.

On the other hand, the X-ray powder diffraction (XRPD) pattern characteristics of crystalline polymorph B are substantially consistent with Table 3 and FIG. 5 .

Form B exists in anhydrous form, eg containing not more than 1.5% by weight of water.

Table 3: X-ray powder diffraction (XRPD) pattern of crystal form B, showing interplanar spacing (d, unit _, ie: Angstrom), characteristic XRPD angle (2θ°) and relative intensity (%)

d-value (_) Angle 2θ° Relative Strength(%) 21.07 4.19 25 10.47 8.44 18 9.656 9.15 1 8.563 10.32 12 7.513 11.77 8 6.616 13.37 8 5.383 16.45 47 5.209 17.01 84 5.063 17.50 5 4.803 18.46 8 4.695 18.89 49 4.548 19.50 19 4.485 19.78 15 4.457 19.90 15 4.390 20.21 4 4.255 20.86 twenty four 4.158 21.35 100 4.009 22.15 20 3.950 22.49 4 3.866 22.99 11

3.811 23.32 12 3.762 23.63 14 3.733 23.82 11 3.618 24.59 12 3.574 24.90 14 3.497 25.45 9 3.468 25.67 twenty two 3.396 26.22 20 3.301 26.99 15 3.218 27.70 twenty one 3.153 28.29 5 3.103 28.75 12 3.052 29.24 4 2.972 30.04 16 2.883 31.00 6 2.863 31.21 16 2.836 31.52 3 2.778 32.20 2 2.742 32.63 16 2.707 33.06 3 2.604 34.42 12 2.578 34.76 6 2.562 35.00 3 2.475 36.27 16 2.422 37.10 1 2.402 37.41 2 2.357 38.15 8 2.343 38.39 10 2.297 39.19 2 2.259 39.87 10

Optionally, crystalline polymorph B is additionally characterized by infrared spectroscopy as shown in FIG. , 1611, 1546, 1513, 1464, 1441, 1416, 1393, 1366, 1333, 1318, 1301, 1284, 1244, 1219, 1181, 1161, 1114, 1097, 1081, 1044, 1030, 994, 948, 924, 896 , 826, 812, 772, 741, 712 cm ^-1 observed spectral bands. Thus, Form B provided an infrared spectrum substantially consistent with FIG. 6 .

In additional aspects, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate A crystalline polymorph wherein 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and phosphate The 1:1 molar ratio, referred to herein as Form B1, has an X-ray powder diffraction (XRPD) pattern characterized by intensity peaks at values of approximately 16.46, 19.51, 19.76, 19.88, and 23.31 in degrees 2-theta. The crystalline polymorph B1 may also exhibit an intensity peak at any one or more of the values expressed in degrees 2-theta selected from the group consisting of about 8.39, 21.36, 23.00, 23.61, 23.80, 24.54, 26.20, and 27.71.

Form B1 exists in anhydrous form, eg containing not more than 1.5% by weight of water.

On the other hand, the X-ray powder diffraction (XRPD) pattern characteristics of the crystalline polymorph B1 are substantially consistent with Table 4 and FIG. 7 .

Table 4: X-ray powder diffraction (XRPD) pattern of crystal form B1, showing interplanar spacing (d, unit _, ie: Angstrom), characteristic XRPD angle (2θ°) and relative intensity (%)

d-value (_) Angle 2θ° Relative Strength(%) 21.06 4.19 14 10.54 8.39 twenty four 9.652 9.16 2 8.585 10.30 20 7.509 11.78 10 6.613 13.38 8 5.381 16.46 100 ^* 5.254 16.86 17 5.197 17.05 19 5.061 17.51 10 4.809 18.43 10 4.692 18.90 twenty one 4.546 19.51 31 4.489 19.76 40 4.452 19.88 41 4.388 20.22 9 4.266 20.81 13 ^* 4.156 21.36 twenty four ^* 4.127 22.52 17 ^* 4.008 22.16 twenty one 3.953 22.47 6 3.864 23.00 27 3.814 23.31 29 3.765 23.61 29 3.736 23.80 29 3.625 24.54 twenty four 3.581 24.85 15 3.504 25.40 13

3.466 25.68 6 3.398 26.20 27 3.299 27.00 11 3.216 27.71 twenty four 3.158 28.24 11 3.102 28.76 14 3.050 29.25 4 2.971 30.06 6 ^* 2.944 30.33 5 ^* 2.890 30.92 5 ^* 2.870 31.13 7 ^* 2.843 31.44 4 ^* 2.790 32.06 4 2.743 32.61 12 2.709 33.05 4 ^* 2.689 33.29 4 ^* 2.658 33.69 1 2.605 34.40 7 2.578 34.77 6 2.563 34.99 6 ^* 2.499 35.91 4 2.476 36.25 10 ^* 2.405 37.36 2 2.356 38.16 6 2.344 38.38 5 2.297 39.18 4 2.258 39.89 2

Optionally, the crystalline polymorph B1 is additionally characterized by infrared spectroscopy as shown in FIG. , 1611, 1546, 1513, 1464, 1441, 1416, 1393, 1366, 1333, 1318, 1301, 1284, 1244, 1219, 1181, 1161, 1114, 1097, 1081, 1044, 1030, 994, 948, 924, 896 , 826, 812, 772, 741, 712 cm ^-1 observed spectral bands. Thus, Form B1 provided an infrared spectrum substantially consistent with FIG. 6 .

The X-ray powder diffraction (XRPD) patterns of Form B1 and Form B differ only in the relative intensities of the patterns, with d-values within a specified measurement accuracy of 0.05 degrees/2Θ. Some reflections of Form B1 have better resolution, thus giving rise to additional reflections, which are marked with an asterisk in Table 4.

Thus, Form B and Form B1 have the same infrared spectrum, but differ in their X-ray powder diffraction (XRPD) patterns, in certain properties such as hygroscopicity, and in their morphology (e.g. how they crystal size) are different. Furthermore, Form B and Form B1 may occur as a mixture.

Forms B and B1 have melting points in the range of 175-176°C (Kofler).

In a further aspect, the present invention provides crystals of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate Shaped polymorphs, wherein the moles of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and phosphate The 1:1 ratio, referred to herein as Form E, has an X-ray powder diffraction (XRPD) pattern characterized by intensity peaks at values of approximately 4.60, 13.39, 18.20, 18.53, and 22.75 in degrees 2-theta. Crystalline polymorph E can also exhibit an intensity peak at any one or more of the values in degrees 2-theta selected from the group consisting of about 22.20, 22.99, 23.24, 24.19, and 30.50.

Form E exists in anhydrous form, eg containing not more than 0.5% by weight of water.

On the other hand, the X-ray powder diffraction (XRPD) pattern characteristics of crystalline polymorph E are substantially consistent with Table 5 and FIG. 8 .

Table 5: X-ray powder diffraction (XRPD) pattern of crystal form E, showing interplanar spacing (d, unit _, ie: Angstrom), characteristic XRPD angle (2θ°) and relative intensity (%)

d-value (_) Angle 2θ° Relative Strength(%) 19.19 4.60 44 10.92 8.09 3 9.570 9.23 2 6.609 13.39 43 6.332 13.97 5 6.263 14.13 5 5.964 14.84 5 5.749 15.40 9 5.450 16.25 2 5.152 17.20 7 5.075 17.46 5 4.870 18.20 27 4.785 18.53 100 4.591 19.32 3 4.382 20.25 3 4.294 20.67 7 4.170 21.29 4

4.123 21.54 5 4.001 22.20 12 3.906 22.75 49 3.865 22.99 20 3.824 23.24 13 3.799 23.40 7 3.757 23.66 9 3.677 24.19 twenty three 3.626 24.53 2 3.606 24.67 2 3.545 25.10 2 3.500 25.43 3 3.477 25.60 3 3.400 26.19 3 3.338 26.68 6 3.308 26.93 1 3.206 27.80 2 3.189 27.96 2 3.108 28.70 1 3.097 28.81 2 3.061 29.15 1 3.011 29.65 4 3.000 29.75 4 2.929 30.50 10 2.861 31.24 4 2.817 31.74 3 2.783 32.14 2 2.729 32.79 2 2.695 33.21 4 2.658 33.69 4 2.641 33.91 5 2.586 34.65 1 2.523 35.55 2 2.493 36.00 1 2.477 36.24 1 2.449 36.67 2 2.388 37.63 5 2.342 38.41 2

Optionally, crystalline polymorph E is additionally characterized by infrared spectroscopy as shown in FIG. , ^{1468,1443,1419,1395,1364,1331,1303,1238,1181,1165,1140,1096,1052,1029,1008,953,906,882,831,819,768,739,714,663} spectral bands were observed. Thus, Form E provided an infrared spectrum substantially consistent with FIG. 9 .

Form E has a melting point in the range of 167-172°C (Kofler).

Phosphate may be obtained as a solvate rather than a hydrate, eg polymorph D, depending on the solvent from which the phosphate is recovered. Such solvates form part of the present invention and references hereinafter to phosphates include their solvates.

Accordingly, in a further aspect, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate A crystalline polymorph of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and phosphate 1:1 molar ratio, referred to herein as Form D, has an X-ray powder diffraction (XRPD) pattern characterized by intensity peaks at values of approximately 14.33, 16.05, 16.36, 21.97, and 22.89 in degrees 2Θ. Crystalline polymorph D may also exhibit an intensity peak at any one or more of the values expressed in degrees 2-theta selected from the group consisting of about 4.75, 15.04, 16.70, 19.26, 19.57, 20.80, 21.97, 22.74, 23.91 and 24.53.

Form D is a solvated form of methanol.

In another aspect, the X-ray powder diffraction (XRPD) pattern characteristics of crystalline polymorph D are substantially consistent with Table 6 and Figure 10 .

Table 6: X-ray powder diffraction (XRPD) pattern of crystal form D, showing interplanar spacing (d, unit _, ie: Angstrom), characteristic XRPD angle (2θ°) and relative intensity (%)

d-value (_) Angle 2θ° Relative Strength(%) 20.76 4.25 twenty four 18.61 4.75 33 12.36 7.15 9 10.70 8.26 12 10.31 8.57 15 9.960 8.87 5 9.193 9.61 8 8.538 10.35 20 7.176 12.33 9 6.852 12.91 15 6.177 14.33 100 5.887 15.04 39

5.517 16.05 40 5.414 16.36 63 5.304 16.70 35 5.135 17.26 26 4.926 17.99 twenty four 4.748 18.67 8 4.605 19.26 31 4.534 19.57 36 4.396 20.18 twenty one 4.312 20.58 twenty four 4.268 20.80 32 4.094 21.69 26 4.043 21.97 41 3.977 22.34 25 3.907 22.74 36 3.882 22.89 43 3.786 23.48 18 3.719 23.91 35 3.672 24.22 42 3.627 24.53 37 3.539 25.14 20 3.448 25.82 28 3.412 26.10 27 3.279 27.18 16 3.246 27.45 12 3.204 27.82 8 3.113 28.66 8 3.036 29.39 10 3.002 29.73 8 2.949 30.29 11 2.931 30.47 12 2.905 30.75 18 2.855 31.31 4 2.730 32.78 13 2.664 33.62 7 2.629 34.08 11 2.564 34.97 4 2.514 35.68 4 2.487 36.08 6 2.473 36.30 5 2.449 36.67 3 2.378 37.81 7 2.307 39.01 11 2.724 32.85 2 2.615 34.27 4

2.570 34.88 3 2.555 35.10 3 2.453 36.61 2 2.419 37.13 2 2.334 38.55 2 2.305 39.04 3 2.276 39.57 3

Optionally, crystalline polymorph D is additionally characterized by infrared spectroscopy as shown in FIG. . A spectral band was observed at ^-1 . Thus, Form D provided an infrared spectrum substantially consistent with FIG. 11 .

Brief description of the drawings:

Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form A

Figure 2 shows the infrared spectrum of Form A

Figure 3 shows the X-ray powder diffraction (XRPD) pattern of Form C

Figure 4 shows the infrared spectrum of Form C

Figure 5 shows the X-ray powder diffraction (XRPD) pattern of Form B

Figure 6 shows the infrared spectra of Form B and Form B1

Figure 7 shows the X-ray powder diffraction (XRPD) pattern of crystal form B1

Figure 8 shows the X-ray powder diffraction (XRPD) pattern of Form E

Figure 9 shows the infrared spectrum of Form E

Figure 10 shows the X-ray powder diffraction (XRPD) pattern of crystal form D

Figure 11 shows the infrared spectrum of Form D

In all figures showing the infrared spectra of phosphate polymorphs, the scale of the abscissa is the wave number (in cm ⁻¹ ), while the ordinate is the transmittance (%). In all figures showing X-ray powder diffraction (XRPD) patterns of phosphate polymorphs, the abscissa is scaled in degrees 2θ (2-theta level), while the ordinate is linear intensity in counts per second (cps) .

The present invention includes said phosphate salt and its crystalline polymorphs A, B, B1, C, D and E, whether isolated in pure form or as a mixture of said polymorphs, or mixed with other substances For example a pharmaceutically acceptable carrier.

Thus, in one aspect there is provided in isolated form 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate Salts and their polymorphs A, B, B1, C, D and E.

In a further aspect, there is provided 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione in substantially pure form Phosphate and its polymorphs A, B, B1, C, D and E.

In another aspect of the present invention, said phosphate salts and polymorphs A, B, B1, C, D and E thereof are provided in the form of mixtures thereof.

The phosphates, preferably phosphate hydrates or phosphate anhydrates, can also be present in non-crystalline, i.e. amorphous form, wherein the amorphous form can be prepared (for example analogously) to conventional methods, for example by preparing a solution in Mixtures containing ketones (such as acetone) or 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2 in alcohols (such as ethanol) and water , 4-thiazolidinedione phosphate solution, and then spray dry the solution. Alternatively, rapid precipitation can also be carried out according to (eg analogously to) known methods.

The invention also comprises said phosphate salts and their polymorphs A, B, B1, C, D and E, e.g. in bulk form, which can be further processed according to (e.g. analogously to) known methods. Processing, such as milling. The invention also encompasses said phosphate salt and polymorphs A, B, B1, C and E thereof in pharmaceutically acceptable form (eg milled form).

Furthermore, the invention relates to processes for the preparation of said phosphate salts and their polymorphs A, B, B1, C, D and E.

Accordingly, the present invention provides a process for the preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, The method comprises 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2 dispersed or suspended or dissolved in a suitable solvent medium, 4-Thiazolidinedione or a salt thereof is reacted with a suitable source of phosphate ions.

Optionally, 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2 can be formed, for example, in the reaction mixture, as described below, A solvate of 4-thiazolidinedione phosphate, wherein the reaction mixture is prepared by mixing 5-[[4-[2-(methyl-2-pyridyl) dispersed or suspended or dissolved in a suitable solvent medium Amino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or a salt thereof and a suitable phosphate ion source as described above.

Optionally, 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazole can be recovered from the reaction mixture as described below The alkanedione phosphate is recovered, preferably in one of its polymorphic forms.

Optionally, the 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, preferably in the form of It exists in a polymorphic form which can be dried, preferably under vacuum.

Optionally, one polymorph can be converted into another polymorph according to (eg analogously to) known methods. For example, under the conditions described below and/or according to the methods described below, Form A can be transformed into Form B or D, Form C can be transformed into Form B or B1, Form D can be transformed into Form A Or B, Forms A, B, B1, D and E can be transformed into Form C.

Alternatively, as described herein, the conversion of one polymorph to another polymorph can be carried out in a reaction mixture by dissolving 5- [[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione is obtained by contacting an appropriate phosphate ion source.

5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, preferably in the form of It exists in a polymorphic form for further processing, eg milling.

In another aspect, the present invention provides for the preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl] in polymorphic form A, B, B1 or E A process for methyl]-2,4-thiazolidinedione phosphate comprising dispersing or suspending or dissolving 5-[[4-[2-(methyl-2- Pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or a salt thereof is reacted with a suitable phosphate ion source, and the following steps are then carried out:

(i) Solvation with optional formation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate things,

(ii) recovery of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate,

(iii) drying the 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate obtained in step (ii) , especially under vacuum, in order to obtain 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl in its polymorphic form A, B, B1 or E ]-2,4-thiazolidinedione phosphate.

Optionally, the phosphate salts and their polymorphs A, B, B1 or E obtained by the process described above can be further processed by known manufacturing methods such as milling methods.

Preferably, phosphoric acid is a suitable source of phosphate ions in the above method.

Alternatively, 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or a salt thereof can be prepared in powder form Add to a suitable phosphate ion source.

In general, phosphate and its polymorphs A, B, B1 or E can be obtained by contacting a stoichiometry such as 1:1 of phosphoric acid and 5-[[4-[2-(methyl-2-pyridylamino) Ethoxy]phenyl]methyl]-2,4-thiazolidinedione, or alternatively phosphoric acid and 5-[[4-[2 -(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione for preparation.

The concentration range of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione is relative to the solvent medium used in the reaction The total amount is preferably a weight/volume ratio of 1-50%, more preferably a weight/volume ratio of 1-10%.

As described above for dissolving, dispersing or suspending 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or Salts thereof and suitable solvent media for reaction with a suitable source of phosphate ions are organic solvent media such as ketones like acetone; or alcohols such as _C1 - _C4 alcohols such as ethanol or methanol; or nitriles such as Acetonitrile; or an ether, such as tetrahydrofuran; or a mixture thereof, or water, or a mixture of said organic solvent and water.

Preference is given to using water as co-solvent. The preferred amount of water is such that the ratio of water to organic solvent medium is 1-100% (V/V), preferably 1-20% (V/V).

A suitable source of phosphate ions is phosphoric acid, e.g. 85% (W/W) phosphoric acid or less, e.g. water or in an organic solvent medium such as a ketone (e.g. acetone) or an alcohol (e.g. _C1 - _C4 alcohol, For example ethanol or methanol) or mixtures of ketones and alcohols are diluted 1:1 to 1:10 W/V. Phosphoric acid is preferably added as such, or in the form of a solution, for example in any one of the aforementioned organic solvent media.

Metaphosphoric acid (preferably in combination with water) or sodium dihydrogenphosphate or potassium dihydrogenphosphate, disodium hydrogenphosphate or dipotassium hydrogenphosphate or trisodium or potassium phosphate in combination with a mineral acid (preferably phosphoric acid) are phosphate ions Alternative sources.

The presence of water is required at some stages in the formation of phosphate hydrates such as Form A. The water may be present in the source of phosphate ions, for example in the phosphoric acid used, for example by using phosphoric acid at a concentration of 85% (w/w) or less; or the water is present in the process as a co-solvent, For example water in a ratio of 1-100% (v/v), preferably 1-20%, to the organic solvent medium.

However, it is also possible to prepare a phosphate hydrate such as Form A by exposing the reaction to atmospheric humidity or by using a non-dehydrating solvent medium such as aqueous acetone or a non-dehydrating phosphate ion source such as 85% (w/w) phosphoric acid. The formation provides enough water.

The reaction can be carried out at room temperature or elevated temperature, eg, from about 35°C to about 60°C, preferably from about 30°C to about 50°C, or at the reflux temperature of the solvent medium, although any convenient temperature can be employed which provides the desired product.

Solvates, preferably hydrates, of phosphate salts can be prepared, for example, by crystallization from a solvent medium as described above, which provides or contains a solvate component, or by exposing the phosphate salt according to (for example analogously to) known methods. Prepared in vapor of the solvated component. As mentioned above, the solvate formation may take place in the reaction mixture.

Recovery of the desired compound, e.g., phosphate (e.g., in its polymorphic form), prior to drying, including isolation from the reaction mixture and/or from a suitable solvent medium; wherein said solvent medium is optionally the above-mentioned solvent medium used in the above-mentioned reaction , preferably water as co-solvent; or alternatively a mixture of said solvent media or different solvent media or mixtures thereof, eg C ₁ -C ₄ alkyl acetate or eg hydrogenated carbon eg hexane. The desired compound can be isolated from the aforementioned reaction mixture and/or solvent medium by filtration according to known methods, and can further comprise a subsequent washing step, which means that the desired compound can be washed in one of the aforementioned solvent media, for example in Ethanol, such as 96% (w/w) ethanol, or in a mixture thereof, such as a mixture of acetone and water, such as a mixture of 95% (v/v) acetone and water.

Alternatively, the desired compound can be isolated by crystallization from the reaction mixture and/or from a suitable solvent medium or mixture of solvent mediums as described above, wherein said crystallization is initiated through the use of seeds. Strict control of the precipitation temperature at about 20°C-80°C to 0°C-20°C and/or the use of seed crystals are important for improving the reproducibility of phosphate salts and their polymorphs such as Forms A, B, B1 and E. useful.

Preferably, the isolated phosphate salts, e.g. polymorphs A, B, B1 and E thereof, are dried under vacuum at room temperature, for example at a temperature of from about 20°C to about 35°C, such as about 25°C; or at an elevated temperature , for example about 35°C to about 80°C, for example about 40°C to about 60°C, preferably about 40°C. Optionally, drying is performed using a desiccant such as phosphorus pentoxide. The drying process is continued until the water content is below about 4.5%, such as 3.58%, such as below 0.1% by weight. The duration of the drying process is not critical and may be, for example, about 10-30 hours, such as 15-25 hours, preferably about 18-20 hours.

In a preferred embodiment, the crystal form A can be prepared by 5-[[4-[2-(methyl-2-pyridylamino) dispersed or suspended or dissolved in a suitable solvent medium such as a mixture of acetone and water ) Ethoxy]phenyl]methyl]-2,4-thiazolidinedione or a salt thereof is prepared by reacting a suitable source of phosphate ions such as 85% phosphoric acid. Optionally, seed crystals of Form A may be added and the resulting mixture may be stirred, eg, for about 3-5 hours, at a temperature as described above, eg, near room temperature.

Subsequently, 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl polymorph Form A can be isolated from the mixture as described above, for example by filtration. ]-2,4-thiazolidinedione phosphate, and may be washed with a suitable solvent medium, for example with a mixture of acetone and water, and may subsequently be dried at a temperature as described above, preferably near room temperature, under vacuum.

In another preferred embodiment, the crystal form B can be obtained by dissolving or suspending or dissolving 5-[[4-[2-(methyl-2-pyridyl) in a suitable solvent medium such as a mixture of acetone and water Amino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or a salt thereof is prepared by reaction with a suitable source of phosphate ion such as 85% phosphoric acid. Optionally, seed crystals of Form B can be added, and the resulting mixture can be stirred for at least about 30 hours at the temperature described above, eg, near room temperature.

Subsequently, 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methanol in its polymorphic form C can be isolated from the mixture as described above, for example by filtration. base]-2,4-thiazolidinedione phosphate, and can be washed with a suitable solvent medium, for example with a mixture of acetone and water, and then can be washed at the temperature mentioned above, preferably at a temperature of about 40° C. and vacuum Drying under , thereby obtaining the crystalline form B, which may contain traces of B1.

In another preferred embodiment, Form B1 may be prepared in a manner similar to that described above for Preparation B, but optionally using seeds of Form B1 instead of Form B and stirring the mixture for at least about 50 hours.

In another preferred embodiment, Form E can be obtained as described above by dissolving or suspending or dissolving 5-[[ 4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or its salt with a suitable phosphate ion source such as 85% phosphoric acid in The reaction proceeds at elevated temperature. The resulting reaction mixture was then cooled to near room temperature with stirring. 5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl polymorph Form E is then isolated from the reaction mixture as described above, for example by filtration. ]-2,4-thiazolidinedione phosphate, and can be washed with a suitable solvent medium, for example ethanol (for example 96% (w/w) ethanol), and then can be washed at the above-mentioned temperature, preferably at Drying is carried out at a temperature of about 40°C and under vacuum.

Form A can be converted to Form B by heating to about 140°C to about 160°C.

In another aspect, the present invention provides a method of preparing polymorphic Form C phosphate, said method comprising the steps of:

(i) 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2 in polymorphic form A, B, B1, D or E, 4-thiazolidinedione phosphate is dispersed or suspended or dissolved in a suitable solvent medium so as to obtain a mixture,

(ii) stirring the mixture obtained in step (i) alternately at about 50° C. for 1 hour, then at 10° C. for 1 hour, for a total of about 3 to about 5 days,

(iii) recovering the product, polymorph C, from the mixture obtained in step (ii), and

(iv) air-drying the product obtained in step (iii).

In relation to the preparation of polymorphs C and D, the term "mixture" as used herein is understood to include a particular compound such as 5-[[4-[2-(methyl-2 - Dispersions, suspensions and/or solutions of pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate in a suitable solvent medium.

Step (ii) of the above method can be carried out by alternately stirring the mixture obtained in step (i), first at a temperature of about 30°C-50°C, preferably about 50°C, for about 1 hour, and then at about 0°C to about 20°C , preferably at a temperature of about 10° C. for about 1 hour, for a total of about 3 to about 5 days. Alternatively, the alternating stirring process can be interrupted at night, the mixture is kept at room temperature, and then the alternating stirring process is continued the next day.

The preferred solvent medium for the above preparation method of Form C is a mixture of acetone and water, for example a mixture of acetone and water in a ratio of about 2:1 (v/v). Step (iii) of the process can be accomplished by first isolating the product, Form C, from the mixture by filtration and then using a mixture of acetone and water, for example in a ratio of acetone and water of about 95:5 (v/v) A mixture of acetone and water washed the product. Preferably, the separation process is carried out from the mixture at a temperature of about 0°C to about 30°C, preferably about 10°C. The air-drying of step (iv) may be performed for about 5 hours to about 20 hours, for example about 10 hours.

The term "air-drying" as used herein is understood to mean drying a compound, such as polymorph C, in open air with about 20% to about 80%, for example about 30% to about 60%, for example about 40% to about 50% relative humidity and a temperature of about 18°C to about 25°C, for example about 22°C.

The crystalline form C prepared by the method can be obtained by carrying out the drying step (iv) at a temperature of about 40° C. or higher, such as about 60° C. to about 80° C., preferably about 50° C., optionally in vacuum, about 5 hours to about 20 hours, for example about 10 hours to convert to Form B1.

Alternatively, Form C can be prepared by a method comprising the following steps:

(i) 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2 of polymorph A, B, B1, D or E, 4-thiazolidinedione phosphate is dissolved or dispersed or suspended in a suitable solvent medium to obtain a mixture,

(ii) adding a suitable source of phosphate ions, such as phosphoric acid, to the mixture obtained in step (i),

(iii) recovering the product, polymorph C, from the mixture obtained in step (ii), and

(iv) air-drying the product obtained in step (iii).

A preferred solvent medium for the above-mentioned alternative preparation method of Form C is a mixture of acetone and water, for example a mixture of acetone and water in a ratio of about 1:1 (v/v). Step (iii) can be accomplished by first isolating the product, Form C, from the mixture by filtration and then using a mixture of acetone and water, for example a mixture of acetone and water in a ratio of about 95:5 (v/v) Wash product. The air-drying of step (iv) may be performed for about 5 hours to about 20 hours, for example about 10 hours.

Form C prepared according to the above alternative method is obtained by drying the crystal obtained in step (iv) at a temperature of about 40°C or higher, such as about 60°C to about 80°C, preferably about 50°C, optionally under vacuum. Form C converts to Form B in about 5 hours to about 20 hours, for example about 10 hours.

In a further aspect, the present invention provides a method of preparing polymorphic Form D phosphate salt, said method comprising the steps of:

(i) 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate in polymorphic form A dissolved or dispersed or suspended in a suitable solvent medium to obtain a mixture,

(ii) heating the mixture obtained in step (i) to a temperature of about 60° C. for 4 hours, then cooling the mixture to near room temperature under stirring,

(iii) recovering the product, polymorph D, from the mixture obtained in step (ii), and

(iv) drying the product obtained in step (iii), preferably in vacuum.

Step (ii) can be accomplished by first heating the mixture obtained in step (i) to a temperature of about 40°C to about 60°C for about 2 hours to 6 hours and then cooling the mixture to near room temperature with stirring. Preferably, step (ii) is carried out at a temperature of about 60°C for about 4 hours.

A preferred suitable solvent medium for use in the above process is methanol.

Step (iii) of the process is accomplished by first isolating the product, Form D, by filtration and then washing it with methanol. The drying in step (iv) may be performed at a temperature of 20°C to about 60°C, preferably about 25°C to about 30°C, for about 5 hours to about 20 hours, for example about 10 hours.

Form D may contain residual solvents, such as methanol; in this case, it is not suitable for use in the pharmaceutical compositions described below. However, Form D can be converted to Form A by exposing it to humidity, eg, a relative humidity of about 60% to about 70%. In addition, Form D can release its residual methanol component after being heated to a temperature of not lower than 60°C, or can be transformed into Form B by heating to a temperature of about 120°C or higher. Both Forms A and B are then suitable for incorporation into pharmaceutical compositions.

Optionally, desired compounds such as phosphate salts (preferably in their polymorphic forms A, B, B1, C, D and E) can be further processed without isolation from the above reaction mixture.

5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione can be obtained according to known methods such as EP-A-0306228 prepared by published methods.

As stated above, the compound of the present invention, ie the phosphate salt and its polymorphs A, B, B1, C and E, possess useful therapeutic properties. Accordingly, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate and polymorphic Use of Forms A, B, B1, C and E or their mixtures as pharmaceutically active substances, eg as medicaments.

The term "phosphate and its polymorphs A, B, B1, C and E" or "5-[[4-[2-(methyl -2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate and its polymorphs A, B, B1, C and E" are understood to mean or These compounds which are (used as) single components or mixtures thereof.

Specifically, the present invention provides phosphate salts and polymorphs A, B, B1, C and E thereof for use in the treatment and/or prevention of hyperglycemia in humans and non-human mammals. More specifically, the present invention provides 5-[[4-[2-(methyl-2-pyridine) for use in the treatment and/or prevention of diabetes in humans or non-human mammals, diabetes-related disorders and certain complications thereof ylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate and its polymorphs A, B, B1, C and E, or mixtures thereof.

As used herein, the term "prevention of diabetes-related conditions" includes treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinemia and gestational diabetes. Preferably, diabetes refers to type II diabetes. Diabetes-related conditions include hyperglycemia, hyperlipidemia, obesity, hypertension, cardiovascular disease, certain eating disorders, polycystic ovary syndrome, and steroid-induced insulin resistance. Herein, diabetes-related complications include kidney disease, especially kidney disease accompanying the progression of type II diabetes, wherein said kidney disease includes diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertension Renal sclerosis and end-stage renal disease.

The phosphate salts and their polymorphic forms A, B, B1, C and E can be administered as such, or preferably as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Therefore, the present invention also provides a phosphate comprising 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, or A pharmaceutical composition of one of its polymorphs A, B, B1, C and E, or their mixture, and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable" as used herein encompasses compounds, compositions and ingredients suitable for both human and veterinary use.

As in conventional pharmaceutical applications, the carrier may contain diluents, fillers, disintegrants, wetting agents, lubricants, coloring agents, flavorings or other conventional adjuvants or vehicles. The term "pharmaceutically acceptable carrier" as used herein is intended to include encapsulating material providing a capsule, either by itself or with other pharmaceutically acceptable carriers, surrounding a pharmaceutically active substance.

The compound of the invention, ie, the phosphate salt and its polymorphic forms A, B, B1, C and E, may be administered by any suitable route, but will generally be administered orally or parenterally.

Pharmaceutical compositions may be prepared by mixing and may be adapted for oral, parenteral or topical administration and may be so formulated as tablets, capsules, oral liquids, powders, granules, lozenges, pastilles , reconstitutable powders, injectable and infusible solutions or suspensions, suppositories and transdermal devices.

Suitable methods for formulating pharmaceutical compositions of phosphate salts and polymorphs A, B, B1, C and E thereof are known.

In addition, the present invention provides 5-[[4-[ 2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, or one of its polymorphs A, B, B1, C and E, or the pharmaceutical composition of their mixture.

In a further aspect, the present invention provides a salt comprising 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, Or a pharmaceutical composition of its polymorphic forms A, B, B1, C and E, or their mixtures for pharmaceutical use.

The present invention also provides a method for treating and/or preventing diabetes in humans or non-human mammals, diabetes-related diseases and certain complications thereof, the method comprising administering 5-[[4 -[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, or polymorphs A, B, B1, C and E , or a mixture thereof. The phosphate, or its polymorphs A, B, B1, C and E, or mixtures thereof are administered in pharmaceutically effective but non-toxic doses.

A pharmaceutically effective amount within the meaning of the present invention includes a dose which provides the desired physiological and/or pharmacological effect.

During the treatment and/or prevention of diabetes, diabetes-related disorders and certain complications thereof, phosphate and its polymorphic forms A, B, B1, C and E can be administered to provide an appropriate dose of 5-[[4-[ Dosages of 2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione are disclosed, for example, in EPA-0306228.

In another aspect, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate and its 5-[[4-[2-(methyl-2-pyridylamino)ethoxy polymorphs A, B, B1, C and E, or mixtures thereof, per se or contained in the pharmaceutical compositions described herein Base] phenyl] methyl] -2,4-thiazolidinedione phosphate and its polymorph A, B, B1, C and E, or its mixture in the preparation of treatment and/or prevention of diabetes, diabetes-related diseases and its use in medicine for some of its complications.

Furthermore, the present invention provides 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4 in combination with one or more antidiabetic agents - Thiazolidinedione phosphate and its polymorphs A, B, B1, C and E, or mixtures thereof in the preparation of medicines for the treatment and/or prevention of diabetes, diabetes-related disorders and certain complications thereof, Such antidiabetic agents are for example biguanides, sulfonylureas and alpha glucosidase inhibitors.

The following examples illustrate the invention without restricting it in any way. All temperatures are given in degrees Celsius and are uncorrected.

The water content was determined by the Karl Fischer method.

The infrared absorption spectra of the phosphate polymorphs described herein were determined with a BRUKERFT IR-Tensor 27.

X-ray powder diffraction (XRPD) pattern is measured under the following conditions:

Equipment: X-ray powder diffractometer D-8 (AXS-BRUKER), θ-θ-goniometer, sample converter; target: copper, Kα1+Kα2λ=1.5406_, parallel beam optics (receiving light Su Lyell focusing Di slit: 0.07mm), scintillation counter, standard sample holder.

Data collection: test tube anode: Cu; generator voltage: 40kV; generator current: 40mA; start angle: 2.0°2θ, end point angle: 40.0°2θ; step size: 0.01°2θ; time per step: 2 seconds; 2θ May differ by 1-3% absolute; 2θ accuracy of sample data: ±0.05 degrees

Ion chromatography (eg determination of phosphoric acid content) was carried out with IC anion column SUPER-SEP commercialized by Metrohm (Switzerland).

Example 1:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph A

Dissolve 5g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione in 250ml acetone and 20ml water at about 30°C in the mixture. The solution was stirred and 1.89 ml of 85% phosphoric acid was added with stirring. Seed crystals of the title compound were added, stirring stopped, and the resulting suspension was allowed to stand at room temperature for approximately 3 hours with stirring for 2-3 minutes every 30 minutes.

The title compound was isolated by aspiration, washed with 25 ml of acetone, and dried in vacuo at room temperature for about 15 hours to obtain a white crystalline solid.

Yield (5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate as polymorph A matter): 5.54g

Water content (Karl Fischer): 1.6% w/w

Phosphoric acid content: 21.7% (by ion chromatography)

Example 2:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph A

Dissolve 25g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione in 1250ml acetone and 100ml water at about 30°C in the mixture. The solution was stirred and 9.45 ml of 85% phosphoric acid was added with stirring. Stirring was stopped and the resulting suspension was left at room temperature for about 18 hours. The resulting suspension was then gently stirred for about 1 hour. The white crystals were then isolated by suction, washed with a mixture of 95 ml of acetone and 5 ml of water, and dried in vacuo at room temperature for about 3 hours.

Yield (5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate as polymorph A matter): 28.56g

Water content (Karl Fischer): 3.3% w/w

The characteristic data of embodiment 2 products:

The infrared absorption spectrum of the solid product obtained in Example 2 is shown in Figure 2, and the observed spectral bands are as described above.

The X-ray powder diffraction (XRPD) spectrum of the solid product obtained in Example 2 is as shown in Figure 1, and Table 1 has recorded interplanar spacing (d, unit _, that is: Angstrom), characteristic XRPD angle (2θ °) and relative strength(%).

Example 3:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph A

Dissolve 10g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione in 500ml 96% ethanol and 50ml water for approx. in a mixture at 60°C. Add 2.1ml of 85% phosphoric acid. A seed crystal of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate was added with stirring and stirring was stopped. The resulting suspension was allowed to stand at room temperature for approximately 3 hours with stirring for 2-3 minutes every 30 minutes. The title compound was isolated by aspiration, washed with two total 50 mL portions of ethanol, and dried in vacuo at room temperature for about 4 days to obtain a white crystalline solid.

Yield (5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate as polymorph A matter): 10.32g

Water content (Karl Fischer): 2.3% w/w

Phosphoric acid content: 20.1% (by ion chromatography)

Example 4:

Dry 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methanol with phosphorus pentoxide base]-2,4-thiazolidinedione phosphate polymorph A

10 g of 5-[[4-[2-(formazol) in polymorph form A with a water content (Karl Fisher) of 2.8% w/w was dried at a temperature of about 45° C. under vacuum in the presence of P ₅ O ₂ . yl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate for about 24 hours.

Water content (Karl Fischer): 0.87% w/w

Example 5:

5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Polymorph A of the acid salt was exposed to humidity

Exposure of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate in polymorphic Form A About 24 hours at different relative humidity.

The results are given in Table 7 below:

Table 7

Water content (Karl Fisher)(%)w/w initially 2.8 45% relative humidity 3.42 63% relative humidity 3.37 86% relative humidity 3.58

Embodiment 6:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph A

Under stirring with a mechanical stirrer, 61.2g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione was dissolved in A mixture of 3060ml acetone and 244.8ml water at 30°C. Add 23.1 ml 85% phosphoric acid. Seeds of Form A were added and the resulting mixture was stirred at a temperature of about 25°C for about 5 hours. The title compound was then isolated by filtration, washed in two 122.4 ml portions of 95% (v/v) acetone/water, and then dried at about 25°C for about 18 hours.

Yield (5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate hydrate as polymorph A matter): 69.1g

Water content (Karl Fischer): 1.7% w/w

Phosphoric acid content: 21.2% (by ion chromatography)

Embodiment 7:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph B

Under stirring with a mechanical stirrer, 20g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione was dissolved in 1000ml A mixture of acetone and 80ml of water at about 25-28°C. 4.16 ml of 85% phosphoric acid (1.1 equivalents) was added. The seeds of Form B were added and the resulting mixture was stirred at a temperature of about 25°C for at least 30 hours. The solid was then isolated by filtration, washed in two 32ml portions of 95% (v/v) acetone/water and dried under vacuum at about 40°C for about 18 hours to obtain the title compound.

Yield (5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate as polymorph B) : 25g (contains trace amount of B1)

Embodiment 8:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph B1

Under stirring with a mechanical stirrer, 20g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione was dissolved in 1000ml A mixture of acetone and 80ml of water at about 25-28°C. 4.16 ml of 85% phosphoric acid (1.1 equivalents) was added. Seeds of Form B1 were added and the resulting mixture was stirred at a temperature of about 25°C for at least 50 hours. The solid was then isolated by filtration, washed in two 32ml portions of 95% (v/v) acetone/water and dried under vacuum at about 40°C for about 18 hours to obtain the title compound.

Yield (5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate as polymorph B1) : About 25g

Embodiment 9:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph B1

5g 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate crystal form A was suspended in 50ml acetone/ in a mixture of water (2:1 v/v). The resulting mixture was alternately stirred throughout the day, first at about 50°C for about 1 hour and then at about 10°C for about 1 hour, while maintaining the mixture at room temperature overnight. This process was repeated for approximately 5 days in total. The solid was then isolated from the suspension (at 10° C.) by filtration, washed with 10 ml of a mixture of acetone/water (95% v/v) and dried in vacuo for about 20 hours to obtain the title compound.

Yield (5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate as polymorph B1) : About 4.3g

Example 10:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate in polymorph C and converted to polymorph B

10g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate crystal form B was dissolved in 50ml of acetone and 50ml of water in a mixture at about 60°C. With stirring, 1.48 ml of 85% phosphoric acid was added. The resulting suspension was cooled to room temperature and stirred for about 3 hours. The product, Form C, was isolated by filtration and washed with a total of 20 ml of acetone/water (95:5 (v/v)), then air-dried (open air, relative humidity about 28%, about 22° C.) for about 20 hours; subsequently, the crystal form C was dried in vacuum at about 40° C. for about 20 hours, thereby producing the crystal form B.

Yield (5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate as polymorph B) : 7.02g

Example 11:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Polymorph C of the phosphate salt and converted to polymorph B1

Suspend 5g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate crystal form A in 50ml of acetone/ in a mixture of water (2:1 v/v). The resulting mixture was alternately stirred throughout the day, first at about 50°C for about 1 hour and then at about 10°C for about 1 hour, while maintaining the mixture at room temperature overnight. This process is repeated for a total of approximately 5 days. The product, form C, was isolated from the suspension (approximately 10° C.) by filtration, washed with 10 ml of acetone/water (95:5 v/v) mixture, and air-dried for approximately 20 hours.

Yield (5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate as polymorph C) : About 4.3g

Drying at approximately 40°C yields Form B1.

Example 12:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph D

Suspend 10g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate (form A) in 150ml MeOH (methanol), and the suspension was heated to about 60° C. for about 4 hours. The resulting suspension first became very thin and then Form D began to crystallize. The suspension was then stirred at room temperature for about 2 more hours and the title compound was isolated by filtration, washed with a total of 10 ml of MeOH and then dried in vacuo for about 20 hours.

Yield (5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate as polymorph D) : About 9.72g

Example 13:

Preparation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Phosphate polymorph E

Dissolve 10 g of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione in 250 ml of near-boiling 96% ethanol . The solution was cooled to approximately 65°C with gentle stirring, and 3.78 ml of 85% phosphoric acid (H ₃ PO ₄ ) was added. The solution was then cooled to room temperature with gentle stirring on a mechanical stirrer. After the addition of phosphoric acid, the solution was stirred at the following temperature for the following times: about 20 minutes at about 43°C, about 30 minutes at about 39°C, about 60 minutes at about 30°C, about 2 hours at about 29°C, and about 2 hours at about 23°C. 22 hours. The title compound was then isolated by filtration, washed in two total 20 ml portions of 96% ethanol (EtOH), and dried in vacuo at about 40°C for about 20 hours.

Yield (5-[[4-[2-(Methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate as polymorph E) : 12.1g

Water content (Karl Fischer): 0.2% w/w

As described herein, the phosphate salts and their polymorphs A, B, B1, C, D and E exhibit good stability. Forms A, B, B1 and E were stress-tested at 80° C. in closed vials for approximately 160 hours according to known methods, and no degradation was observed by HPLC testing using standard methods.

Furthermore, the applicant has found that 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate according to the invention Salt and its polymorphs A, B, B1, C, D and E exhibit comparable or even more rapid (expressed) water solubility than rosiglitazone maleate, wherein the maleate Rosiglitazone is currently the main form of rosiglitazone marketed as the active substance in pharmaceutical preparations. For example, Form A exhibits enhanced aqueous solubility, for example about twice that of the maleate salt form, which is useful and interesting for industrial applications.

Furthermore, the methods for producing said phosphate salts and their polymorphs A, B, B1, C, D and E are relatively simple.

Claims (36)

1. The salt of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione and phosphoric acid, or its solvate or non- solvated form. 2. The salt according to claim 1 or its solvate or unsolvate form, wherein said salt is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]benzene Base] methyl]-2,4-thiazolidinedione phosphate, wherein 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2, The molar ratio of 4-thiazolidinedione and phosphate is 1:1. 3. The crystalline polymorph A of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-thiazolidinedione phosphate hydrate, characterized by an X-ray powder diffraction (XRPD) pattern having intensity peaks at values in degrees 2-theta of approximately 15.63, 15.75, 17.30, 19.61 and 21.47. 4. The crystalline polymorph A of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-thiazolidinedione phosphate hydrate, characterized in that the X-ray powder diffraction (XRPD) pattern is basically consistent with Table 1 and Figure 1. 5. The crystalline polymorph A according to claim 3 or 4, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl] - 2,4-thiazolidinedione phosphate hydrate characterized by an infrared spectrum at 2704, 1748, 1701, 1643, 1611, 1546, 1513, 1469, 1420, 1391, 1330, 1302, 1244, 1110, 1028, 928 , 821, 767, 716 cm ^-1 observed bands. 6. The crystalline polymorph B of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-Thiazolidinedione phosphate salt characterized by an X-ray powder diffraction (XRPD) pattern having intensity peaks at values of approximately 4.19, 16.45, 17.01, 18.89 and 21.35 in degrees 2-theta. 7. The crystalline polymorph B of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-thiazolidinedione phosphate, characterized in that the X-ray powder diffraction (XRPD) pattern is basically consistent with Table 3 and Figure 5. 8. The crystalline polymorph B according to claim 6 or 7, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl] - 2,4-thiazolidinedione phosphate characterized by an infrared spectrum at 3050, 2875, 2455, 2325, 2165, 2141, 2114, 2051, 1982, 1874, 1750, 1697, 1640, 1611, 1546, 1513, 1464 , 1441, 1416, 1393, 1366, 1333, 1318, 1301, 1284, 1244, 1219, 1181, 1161, 1114, 1097, 1081, 1044, 1030, 994, 948, 924, 896, 826, 812, 772, 741 , A band was observed at 712cm ^-1 . 9. The crystalline polymorph B1 of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-Thiazolidinedione phosphate salt characterized by an X-ray powder diffraction (XRPD) pattern having intensity peaks at values in degrees 2-theta of approximately 16.46, 19.51, 19.76, 19.88 and 23.31. 10. The crystalline polymorph B1 of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-thiazolidinedione phosphate, characterized in that the X-ray powder diffraction (XRPD) pattern is basically consistent with Table 4 and Figure 7. 11. The crystalline polymorph B1 according to claim 9 or 10, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl] - 2,4-thiazolidinedione phosphate characterized by an infrared spectrum at 3050, 2875, 2455, 2325, 2165, 2141, 2114, 2051, 1982, 1874, 1750, 1697, 1640, 1611, 1546, 1513, 1464 , 1441, 1416, 1393, 1366, 1333, 1318, 1301, 1284, 1244, 1219, 1181, 1161, 1114, 1097, 1081, 1044, 1030, 994, 948, 924, 896, 826, 812, 772, 741 , A band was observed at 712cm ^-1 . 12. The crystalline polymorph C of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-Thiazolidinedione phosphate hydrate, characterized by an X-ray powder diffraction (XRPD) pattern having intensity peaks at values in degrees 2-theta of approximately 12.86, 15.98, 16.26, 21.60 and 24.50. 13. The crystalline polymorph C of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-thiazolidinedione phosphate, characterized in that the X-ray powder diffraction (XRPD) pattern is basically consistent with Table 2 and Figure 3. 14. The crystalline polymorph C according to claim 12 or 13, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl] - 2,4-thiazolidinedione phosphate characterized by infrared spectra at 3111, 2924, 2652, 2325, 2165, 2114, 2051, 1981, 1874, 1745, 1698, 1641, 1608, 1541, 1513, 1464, 1443 , 1416, 1392, 1363, 1332, 1301, 1265, 1249, 1218, 1179, 1163, 1113, 1096, 1048, 1028, 995, 951, 926, 905, 823, 812, 774, 739, ^{713cm -1} observation to the band. 15. The crystalline polymorph D of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-Thiazolidinedione phosphate salt characterized by an X-ray powder diffraction (XRPD) pattern having intensity peaks at values in degrees 2-theta of approximately 14.33, 16.05, 16.36, 21.97 and 22.89. 16. The crystalline polymorph D of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-thiazolidinedione phosphate, characterized in that the X-ray powder diffraction (XRPD) pattern is basically consistent with Table 6 and Figure 10. 17. The crystalline polymorph D according to claim 15 or 16, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl] - 2,4-thiazolidinedione phosphate characterized by infrared spectra at 3129, 2933, 2684, 2325, 2165, 2150, 2113, 2051, 1982, 1743, 1699, 1641, 1604, 1538, 1511, 1467, 1446 , 1412, 1389, 1357, 1332, 1303, 1279, 1242, 1164, 1107, 1077, 1063, 1021, 994, 956, 928, 903, 832, 802, 769, 739, 719cm ^-1 observed bands. 18. The crystalline polymorph E of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-Thiazolidinedione phosphate salt characterized by an X-ray powder diffraction (XRPD) pattern having intensity peaks at values in degrees 2-theta of approximately 4.60, 13.39, 18.20, 18.53 and 22.75. 19. The crystalline polymorph E of the salt according to claim 1 or 2, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl ]-2,4-thiazolidinedione phosphate, characterized in that the X-ray powder diffraction (XRPD) pattern is basically consistent with Table 5 and Figure 8. 20. The crystalline polymorph E according to claim 18 or 19, which is 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl] - 2,4-thiazolidinedione phosphate characterized by infrared spectra at 2918, 2702, 2417, 2324, 2165, 2051, 1982, 1752, 1700, 1642, 1610, 1546, 1512, 1468, 1443, 1419, 1395 , 1364, 1331, 1303, 1238, 1181, 1165, 1140, 1096, 1052, 1029, 1008, 953, 906, 882, 831, 819, 768, 739, 714, 663 cm ^-1 bands were observed. 21. The compound of any one of claims 1-20, in isolated form. 22. The compound of any one of claims 1-20, in substantially pure form. 23. The method for preparing the salt according to claim 1 or 2, which comprises dispersing or suspending or dissolving 5-[[4-[2-(methyl-2-pyridylamino)ethoxy Base]phenyl]methyl]-2,4-thiazolidinedione or a salt thereof is reacted with an appropriate source of phosphate ion. 24. The method for preparing the crystalline polymorph A, B, B1 or E according to any one of claims 3-5, 6-8, 9-11 or 18-20, comprising dispersing or suspending Or 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or its salt dissolved in a suitable solvent medium and Appropriate phosphate ion source reaction followed by the following steps: (i) Solvation with optional formation of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate things, (ii) recovery of 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate, (iii) drying the 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate obtained in step ii), In particular drying under vacuum in order to obtain 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl] in polymorphic form A, B, B1 or E - 2,4-thiazolidinedione phosphate. 25. A method according to claim 23 or 24, wherein the source of suitable phosphate ions is phosphoric acid. 26. A process for the preparation of crystalline polymorph C according to any one of claims 12-14, comprising the steps of: (i) 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2 in polymorphic form A, B, B1, D or E, 4-thiazolidinedione phosphate is dispersed or suspended or dissolved in a suitable solvent medium so as to obtain a mixture, (ii) stirring the mixture obtained in step (i) alternately, first at about 50° C. for about 1 hour, then at about 10° C. for about 1 hour, for about 3 days to about 5 days, (iii) recovering the product, polymorph C, from the mixture obtained in step (ii), and (iv) air-drying the product obtained in step (iii). 27. A process for the preparation of crystalline polymorph C according to any one of claims 12-14, comprising the steps of: (i) 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2 in polymorphic form A, B, B1, D or E, 4-thiazolidinedione phosphate is dissolved or dispersed or suspended in a suitable solvent medium so as to obtain a mixture, (ii) adding a suitable source of phosphate ions, such as phosphoric acid, to the mixture obtained in step (i), (iii) recovering the product, polymorph C, from the mixture obtained in step (ii), and (iv) air-drying the product obtained in step (iii). 28. The method according to claim 26 or 27, wherein the suitable solvent medium is a mixture of acetone and water. 29. A process for preparing the crystalline polymorph D according to any one of claims 15-17, comprising the steps of: (i) 5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione phosphate in polymorphic form A dissolved or dispersed or suspended in a suitable solvent medium in order to obtain a mixture, (ii) heating the mixture obtained in step (i) to a temperature of about 60° C. for about 4 hours, then cooling the mixture to near room temperature with stirring, (iii) recovering the product, polymorph D, from the mixture obtained in step (ii), and (iv) drying the product obtained in step (iii), preferably in vacuum. 30. The method of claim 29, wherein the suitable solvent medium is methanol. 31. A compound according to any one of claims 1-14 and 18-20, or a mixture thereof, for use as a medicament. 32. The use of the compound or mixture thereof according to any one of claims 1-14 and 18-20, for the preparation of treatment and/or prevention of diabetes in humans or non-human mammals, diabetes-related disorders and certain complications thereof disease drugs. 33. A pharmaceutical composition comprising a compound or mixture thereof according to any one of claims 1-14 and 18-20, and a pharmaceutically acceptable carrier. 34. A pharmaceutical composition comprising a compound of any one of claims 1-14 and 18-20, or a mixture thereof, in combination with one or more other antidiabetic agents, and a pharmaceutically acceptable carrier. 35. A method for treating and/or preventing diabetes, diabetes-related disorders and certain complications thereof, comprising administering the drug according to any one of claims 1-14 and 18-20 to a human in need or a non-human mammal compounds or mixtures thereof. 36. A method of treating and/or preventing diabetes, diabetes-related disorders and certain complications thereof, comprising administering a pharmaceutical composition according to claim 33 or 34 to a human or non-human mammal in need thereof.

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