WO2003050112A1

WO2003050112A1 - Toluenesulfonate hydrates of a thiazolidinedione derivative

Info

Publication number: WO2003050112A1
Application number: PCT/GB2002/005672
Authority: WO
Inventors: Andrew Simon Craig; Tim Chien Ting Ho
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 2001-12-13
Filing date: 2002-12-13
Publication date: 2003-06-19
Anticipated expiration: 2004-06-13
Also published as: AU2002350965A1

Abstract

A 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione p-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate), a process for preparing such a salt, a pharmaceutical composition containing such as salt and the use of such a salt in medicine.

Description

TOLUENESULFONATE HYDRATES OF A THIAZOLIDINEDIONE DERIVATIVE

This invention relates to a novel pharmaceutical, to a process for the preparation of the pharmaceutical and to the use of the pharmaceutical in medicine. EP-A-0 306 228 relates to certain thiazolidinedione derivatives disclosed as having hypoglycaemic and hypolipidaemic activity. The compound of Example 30 of EP-A-0 306 228 is 5-[4-[2-(N-methyl-N- (2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter referred to as "Compound (I)").

WO 94/05659 discloses certain salts of the compounds of EP-A-0 306 228. The preferred salt of WO 94/05659 is the maleic acid salt.

There remains a need for alternative salt forms which have properties suitable for pharmaceutical processing on a commercial scale.

We have now prepared and characterised a para-toluenesulfonate salt of Compound (I) in hydrated form (hereinafter also referred to as the "Toluenesulfonate Hydrate") that is particularly stable and hence is suitable for bulk preparation and handling. Further, we have characterised two distinct hydrated forms, referred to herein as Hydrate 1 and Hydrate 2.

The novel hydrates are high melting crystalline materials and hence amenable to large scale pharmaceutical processing, especially in manufacturing processes which require or generate heat, for example milling, fluid bed drying, spray drying, hot melt processing and sterilisation by autoclaving. Further, the novel hydrates have low solubilty and so are amenable to processing by wet milling.

The novel salts can be prepared by an efficient and economic process particularly suited to large-scale preparation. The novel Toluenesulfonate Hydrate also has useful pharmaceutical properties and in particular it is indicated to be useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

Accordingly, the present invention provides a 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7-toluenesulfonate salt hydrate as a novel compound.

In one aspect of this invention, the Toluenesulfonate Hydrate has been reproducibly isolated as a hydrate containing variously from 3.0-3.5% by wt. water (hereinafter also referred to as "Hydrate 1") which is consistent with a monohydrate (1 molar equivalent of H O = 3.3% by wt.) Accordingly, the present invention also provides a 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/?-toluenesulfonate monohydrate as a novel compound. However, since the water content may not be fixed to exactly 1.0 molar equivalent (3.3% by wt), in one suitable embodiment there is provided a Toluenesulfonate Hydrate 1 characterised by:

(i) an infrared spectrum containing peaks at about 1748, 1347, 1257, 1249, 1064 cm"l; and/or

(ii) a Raman spectrum containing peaks at about 2892, 1735, 1121, 474 cm" 1 ; and/or (iii) an X-ray powder diffraction (XRPD) pattern containing peaks at about 8.4, 12.2, 20.5, 22.8, 33.6 degrees 20; and/or

(iv) a Solid State ¹³C NMR spectrum containing peaks at about 19.3, 43.6, 52.6, 57.9, 66.9 ppm.

In one favoured aspect, the Toluenesulfonate Hydrate 1 provides an infrared spectrum substantially in accordance with Figure 1.

In one favoured aspect, the Toluenesulfonate Hydrate 1 provides a Raman spectrum substantially in accordance with Figure 2. In one favoured aspect, the Toluenesulfonate Hydrate 1 provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3.

In one favoured aspect, the Toluenesulfonate Hydrate 1 provides a Solid State ¹³C NMR spectrum substantially in accordance with Figure 4.

In a further favoured aspect the Toluenesulfonate Hydrate 1 , provides a melting point in the range of 150 to 165°C, such as 152 to 159°C, for example 156°C. In a preferred aspect, the invention provides a 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione toluenesulfonate hydrate, characterised in that it provides:

(i) an infrared spectrum substantially in accordance with Figure 1 ; and (ii) a Raman spectrum substantially in accordance with Figure 2; and

(iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3; and

(iv) a Solid State C NMR spectrum substantially in accordance with Figure 4. In another aspect of this invention, the Toluenesulfonate Hydrate has been reproducibly isolated as a hydrate containing approximately 0.1 to 2.0% by weight water (hereinafter also referred to as "Hydrate 2"). A particular example of Toluenesulfonate Hydrate 2 contains approximately 0.6% by weight water, consistent with 1 :0.17 hydrate.

Additionally a further example contains 1.5% by weight which is consistent with a 1:0.46 hydrate. Accordingly, the present invention provides a 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7-toluenesulfonate containing approximately 0.1 - 2.0% by weight water, preferably 0.4 - 1.6% by weight water, as a novel compound. Alternatively the present invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione j-toluenesulfonate which is a 1 :0.03 - 1 :0.6 hydrate, for example a range from 1 :0.17 to 1 :0.46 hydrate, as a novel compound.

However, since the water content may not be fixed to the amounts indicated above, in one suitable embodiment there is provided a Toluenesulfonate Hydrate 2 characterised by:

(i) an infrared spectrum containing peaks at about 1743, 1699, 1245 and 556 cm" ; and/or

(ii) a Raman spectrum containing peaks at about 2873, 1750, 990, and 890 cm-¹; and/or (iii) an X-ray powder diffraction (XRPD) pattern containing peaks at about 13.0, 13.9, 14.6, 16.6 and 19.5 degrees 2Θ; and/or

(iv) a Solid State ¹³C NMR spectrum containing peaks at about 41.9, 55.8, 68.3, 173.5 ppm

In one favoured aspect, the Toluenesulfonate Hydrate 2 provides an infrared spectrum substantially in accordance with Figure 5.

In one favoured aspect, the Toluenesulfonate Hydrate 2 provides a Raman spectrum substantially in accordance with Figure 6.

In one favoured aspect, the Toluenesulfonate Hydrate 2 provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7. In one favoured aspect, the Toluenesulfonate Hydrate 2 provides a Solid State ¹³C

NMR spectrum substantially in accordance with Figure 8.

In a further favoured aspect the Toluenesulfonate Hydrate 2, provides a melting point in the range of 150 to 165°C, such as 152 to 159°C, for example 153°C.

In a preferred aspect, the invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione Toluenesulfonate Hydrate 2, characterised in that it provides:

(i) an infrared spectrum substantially in accordance with Figure 5; and (ii) a Raman spectrum substantially in accordance with Figure 6; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7; and

(iv) a Solid State ¹³C NMR spectrum substantially in accordance with Figure 8.

The present invention encompasses Toluenesulfonate Hydrate isolated in pure form or when admixed with other materials.

Thus in one aspect there is provided Toluenesulfonate Hydrate in isolated form. In a further aspect there is provided Toluenesulfonate Hydrate in substantially pure form.

In yet a further aspect there is provided Toluenesulfonate Hydrate in crystalline form. Also, the invention provides the Toluenesulfonate Hydrate in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.

Moreover, the invention also provides the Toluenesulfonate Hydrate in a pharmaceutically acceptable form, especially in bulk form, such form being particularly capable of pharmaceutical processing, especially in manufacturing processes which require or generate heat, for example milling; for example heat-drying especially fluid-bed drying or a spray drying; for example hot melt processing; for example heat-sterilisation such as autoclaving; or alternatively for wet-milling. Examples of manufacturing processes which require or generate heat include milling, heat-drying especially fluid-bed drying, spray drying or hot melt processing and heat-sterilisation such as autoclaving. Particular examples of manufacturing processes which require or generate heat include milling, heat-drying especially fluid-bed drying, spray drying and heat-sterilisation such as autoclaving. Furthermore, the invention provides the Toluenesulfonate Hydrate in a pharmaceutically acceptable form, especially in a bulk form and especially in a form having been processed in a manufacturing process requiring or generating heat, for example in a milled form; for example in a heat-dried form, especially a fluid-bed dried or a spray dried formexample in a form having being hot melt processed; for example in a form having being heat-sterilised by such as autoclaving.

The invention also provides the Toluenesulfonate Hydrate in a pharmaceutically acceptable form, especially in bulk form, such form having good flow properties, especially good bulk flow properties.

Suitable texts decribing the manufacturing processes referred to herein include "The Theory and Practice of Industrial Pharmacy" edited by Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig, published by Lea & Febiger and for spray drying and fluid bed drying "Advanced Drying Technologies" by Kudra, Tadeusz.; Mujumdar, A. S, New York Marcel Dekker, Inc., 2001.

The invention also provides a process for preparing the Toluenesulfonate Hydrate, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione (Compound (I)) or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a suitable source ofp-toluenesulfonate ion in the presence of water; and optionally thereafter as required: (i) forming a solvate thereof; (ii) recovering the Toluenesulfonate Hydrate; (iii) drying the product so obtained; and

(iii) further processing the Toluenesulfonate Hydrate in a manufacturing process requiring or generating heat. Formation of Hydrate 1 requires the presence of water at some stage; water may be added as a cosolvent in the process e.g. 5 to 100 % water. However, it is also possible to provide sufficient water for hydrate formation by carrying out the reaction with exposure to atmospheric moisture, or by use of non-anhydrous solvents.

The invention also provides a process for preparing the Toluenesulfonate Hydrate 2, characterised in that Toluenesulfonate Hydrate 1 is prepared and recovered, and then dried under vacuum to obtain Hydate 2.

Preferably, to prepare the Hydrate 2, the isolated Toluenesulfonate Hydrate 1 is dried under vacuum at an elevated temperature i.e. above room temperature, for example in a vacuum oven at 40-100°C, preferrably 40-60°C. The drying is optionally carried out over a dessicant, such as phosphorus pentoxide, and also preferably for an extended period, typically 12 hours or more, for example 16 to 50 hours, to give a product with a water content at about 0.1 - 2.0% by weight, for example a range from 0.4 to 1.6% by weight. A suitable reaction solvent for the preparation of Hydrate 1 is a ketone, such as acetone, an ether such as tetrahydrofuran, an alkanol, such as propan-2-ol, or a hydrocarbon, such as toluene, an ester, such as ethyl acetate, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane or water, or an organic acid such as acetic acid; or a mixture thereof. Conveniently, the source of 7-toluenesulfonate ion is 7-toluenesulfonic acid. The _jP-toluenesulfonic acid may be added as a solid or in solution, for example in water, ether, ketone, nitrile or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.

For example, a solution of 7-toluenesulfonic acid, in particular /7-toluenesulfonic acid monohydrate, in acetone or tetrahydrofuran may be added to a solution of Compound (I) in the same solvent.

An alternative source of /7-toluenesulfonate ion may be provided by a base salt of /7-toluenesulfonic acid for example ammonium /7-toluenesulfonate, or the /7-toluenesulfonic acid salt of an amine, for example ethylamine or diethylamine. The concentration of Compound (I) is preferably in the range 3 to 50% weight/volume, more preferably in the range 5 to 20%. The concentration of /?- toluenesulfonic acid solutions are preferably in the range of 5 to 75% weight/volume.

The reaction is usually carried out at ambient temperature or at an elevated temperature, for example at the reflux temperature of the solvent, although any convenient temperature that provides the required product may be employed.

Recovery of the required compound generally comprises crystallisation from an appropriate solvent, conveniently the reaction solvent, usually assisted by cooling. For example, the Toluenesulfonate Hydrate may be crystallised from a ketone such as acetone or a hydrocarbon such as toluene. An improved yield of the salt may be obtained by evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling. Cosolvents can be added to reduce the solubility of the product in the solvent system to provide a good yield, e.g. diethyl ether, diisopropyl ether and heptane. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the product form.

Crystallisation can also be initiated by seeding with crystals of the Toluenesulfonate Hydrate but this is not essential.

Suitable manufacturing processes requiring or generating heat include milling, heat-drying, especially a fluid-bed drying, hot melt processing or heat-sterilisation, such as autoclaving.

Compound (I) is prepared according to known procedures, such as those disclosed in EP-A-0 306 228 and WO 94/05659. The disclosures of EP-A-0 306 228 and WO

94/05659 are incorporated herein by reference. Para-toluenesulfonic acid is a commercially available compound.

When used herein the term "T_onset" is generally determined by Differential

Scanning Calorimetry and has a meaning generally understood in the art, as for example expressed in "Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989 as "The temperature corresponding to the intersection of the pre-transition baseline with the extrapolated leading edge of the transition".

When used herein the term 'prophylaxis of conditions associated with diabetes mellitus' includes the treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinaemia and gestational diabetes.

Diabetes mellitus preferably means Type II diabetes mellitus. Conditions associated with diabetes include hyperglycaemia and insulin resistance and obesity. Further conditions associated with diabetes include hypertension, cardiovascular disease, especially atherosclerosis, certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia. Additional conditions associated with diabetes include polycystic ovarian syndrome and steroid induced insulin resistance.

The complications of conditions associated with diabetes mellitus encompassed herein includes renal disease, especially renal disease associated with the development of Type II diabetes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease.

As mentioned above the compound of the invention has useful therapeutic properties: The present invention accordingly provides the Toluenesulfonate Hydrate for use as an active therapeutic substance. More particularly, the present invention provides the Toluenesulfonate Hydrate for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

The Toluenesulfonate Hydrate may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the Toluenesulfonate Hydrate are generally those disclosed for Compound (I) in the above mentioned publications.

Accordingly, the present invention also provides a pharmaceutical composition comprising the Toluenesulfonate Hydrate and a pharmaceutically acceptable carrier therefor.

The Toluenesulfonate Hydrate is normally administered in unit dosage form.

The active compound may be administered by any suitable route but usually by the oral or parenteral routes. For such use, the compound will normally be employed in the form of a pharmaceutical composition in association with a pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.

Compositions are prepared by admixture and are suitably adapted for oral, parenteral or topical administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, pastilles, reconstitutable powders, injectable and infusable solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl toluenesulfonate.

Solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl/7-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active compound.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

The present invention further provides a method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of Toluenesulfonate Hydrate to a human or non-human mammal in need thereof.

Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.

In a further aspect the present invention provides the use of Toluenesulfonate Hydrate for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof. In the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof the Toluenesulfonate Hydrate or a pharmaceutically acceptable solvate thereof may be taken in amounts so as to provide Compound (I) in suitable doses, such as those disclosed in EP 0,306,228, WO94/05659 or WO98/55122.

The unit dose compositions of the invention comprise the Toluenesulfonate Hydrate in an amount providing up to 12 mg, including 1-12 mg such as 2-12 mg of Compound (I), especially 2-4 mg, 4-8 mg or 8-12 mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of Compound (I). Thus in particular there is provided a pharmaceutical composition comprising the Toluenesulfonate Hydrate and a pharmaceutically acceptable carrier therefor, wherein the Toluenesulfonate Hydrate is present in an amount providing 1, 2, 4, 8, 12, 4 to 8 or 8 to 12 mg of Compound (I); such as 1 mg of Compound (I); such as 2 mg of Compound (I); such as 4 mg of Compound (I); such as 8 mg of Compound (I); such as 12 mg of Compound (I).

The invention also provides a pharmaceutical composition comprising the Toluenesulfonate Hydrate in combination with one or more other anti-diabetic agents and optionally a pharmaceutically acceptable carrier therefor. The invention also provides a method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of the Toluenesulfonate Hydrate in combination with one or more other anti-diabetic agents. In a further aspect the present invention provides the use of the Toluenesulfonate

Hydrate in combination with one or more other anti-diabetic agents, for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

In the above mentioned treatments the administration of the Toluenesulfonate Hydrate and the other anti-diabetic agent or agents includes co-administration or sequential administration of the active agents.

Suitably in the above mentioned compositions, including unit doses, or treatments the Toluenesulfonate Hydrate is present in an amount providing up to 12 mg, including 1- 12 mg, such as 2-12 mg of Compound (I), especially 2-4 mg, 4-8 mg or 8-12 mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg of Compound (I) or 4 to 8 or 8 to 12 mg of Compound (I). Thus for example in the above mentioned compositions, including unit doses, or treatments the Toluenesulfonate Hydrate is present in an amount providing 1 mg of Compound (I); the Toluenesulfonate Hydrate is present in an amount providing 2 mg of Compound (I); the Toluenesulfonate Hydrate is present in an amount providing 3 mg of Compound (I); the Toluenesulfonate Hydrate is present in an amount providing 4 mg of Compound (I); or the Toluenesulfonate Hydrate is present in an amount providing 8 mg of Compound (I). The other antidiabetic agents are suitably selected from biguanides, sulphonylureas and alpha glucosidase inhibitors. The other antidiabetic agent is suitably a biguanide. The other antidiabetic agent is suitably a sulphonylurea. The other antidiabetic agent is suitably an alpha glucosidase inhibitor. Suitable antidiabetic agents are those disclosed in WO98/57649, WO98/57634, WO98/57635, WO98/57636, WO99/03477, WO99/03476. The contents of the above mentioned publications are incorporated herein by reference as if set out in full herein.

No adverse toxicological effects are indicated in the above mentioned treatments for the compounds of the invention. The following examples illustrate the invention but do not limit it in any way.

Example 1 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione 7-toluenesulfonate hydrate 1

A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (2.6 g) and acetone (55 ml) was stirred and heated to reflux until a clear solution was observed. A solution of /7-toluenesulfonic acid monohydrate (1.4 g) in acetone (10 ml) was added and the resulting mixture heated to reflux for 10 minutes and then cooled to 22°C. After standing at 22°C in an unsealed vessel for 17 days the product was collected to give 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7- toluensulfonate hydrate 1 (4.2 g) as a crystalline solid.

1H-NMR (d⁶-DMSO): consistent with 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate.

Example 2 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione p-toluenesulfonate hydrate 1

A solution of 7-toluenesulfonic acid monohydrate (5.3 g) in tetrahydrofuran (18 ml) was added to a stirred solution of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (10.0 g) in tetrahydrofuran (100 ml) and water (25 ml). M-Heptane (200 ml) was added followed by diethyl ether (100 ml) and the mixture stirred and heated to reflux and then cooled to 21°C over approximately 30 minutes. The product was collected by filtration and dried under vacuum over phosphorus pentoxide for 1.5 hours to give 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione 7-toluenesulfonate hydrate 1 (15.9 g) as a white crystalline solid.

Water content (Karl Fisher): 3.4% wt/wt

Example 3 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione 7-toluenesulfonate hydrate 1

A solution of /7-toluenesulfonic acid monohydrate (5.3 g) in acetone (15 ml) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione (10.0 g) in a mixture of acetone (100 ml) and water (25 ml). The mixture was heated to reflux until a clear solution was observed and then cooled to 40°C. w-Heptane (100 ml) and diisopropylether (100 ml) were added and the reaction mixture heated to reflux and then cooled to 21°C. Stirring was continued at this temperature until crystallisation was complete. The product was collected by filtration, washed with diisopropylether (50 ml) and dried under vacuum, over phosphorus pentoxide for 2 hours to give 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7- toluenesulfonate hydrate 1 (13.5 g) as a white crystalline solid.

Η-NMR (d⁶-DMSO): consistent with 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate.

Water content (Karl Fisher): 3.1% wt/wt

Example 4 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione/7-toluenesu!fonate hydrate 1

A solution of /7-toluenesulfonic acid monohydrate (5.3 g) in acetone (12.5 ml) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (10.0 g) in a mixture of acetone (100 ml) and water (25 ml). The mixture was heated at reflux for 1 hour, then cooled to 21°C. Diethyl ether (130 ml) was added at 21°C and the reaction mixture heated to reflux for 30 minutes, then cooled to 21°C and stirred for 19 hours at 21°C. The white solid was collected by filtration, washed with acetone (50 ml) and dried on filter for 20 minutes to give 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7- toluenesulfonate hydrate 1 (13.1 g) as a white crystalline solid. Water content (Karl Fisher): 3.3 % wt/wt

Example 5 5-[4-[2-(N-methyI-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione p-toluenesulfonate hydrate 1

A stirred mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (3.0 g) and /7-toluenesulfonic acid monohydrate (2.39 g) in water (60 ml) was heated to reflux to give a clear solution. The solution was then cooled to 21°C over approximately 40 minutes. The solid was collected by filtration, washed with water and dried on filter for 90 minutes to afford 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione /7-toluenesulfonate hydrate 1 (4.6 g) as a white crystalline solid.

Characterising data recorded for the product of Example 1

The infrared absorption spectrum of a mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cm^"1 resolution (Figure 1). Data were digitised at 1 cm^'1 intervals. Bands were observed at: 3481, 3322, 2923, 2855, 1748, 1690, 1639, 1617, 1543, 1509, 1460, 1418, 1378, 1347, 1329, 1296, 1282, 1257, 1249, 1235, 1213, 1178, 1160, 1118, 1078, 1064, 1031, 1009, 936, 898, 828, 822, 815, 779, 740, 717, 686, 649, 609, 562 cm^-1.

The infrared spectrum of the solid product was recorded using Perkin-Elmer Spectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands were observed at: 3492, 3329, 3124, 3062, 2923, 2875, 1748, 1690, 1639, 1617, 1543, 1510, 1475, 1459, 1443, 1418, 1390, 1347, 1329, 1296, 1283, 1248, 1234, 1213, 1178, 1160, 1118, 1078, 1064, 1048, 1031, 1008, 935, 898, 841, 813, 778, 740, 715, 681 cm^"1.

The Raman spectrum of the product (Figure 2) was recorded with the sample in an NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm^"1 resolution with excitation from a Nd:V04 laser (1064 run) with a power output of 400mW. Bands were observed at 3126, 3104, 3076, 3060, 3039, 2961, 2922, 2892, 1735, 1610, 1583, 1544, 1460, 1445, 1418, 1389, 1358, 1332, 1296, 1282, 1266, 1236, 1213, 1204, 1179, 1121, 1034, 1011, 984, 966, 935, 900, 840, 820, 800, 743, 723, 655, 637, 617, 607, 561, 509, 474, 437, 422, 399, 341, 295, 227, 89, 77 cm^"1. The X-Ray Powder Diffractogram pattern of the product (Figure 3) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kV, Generator current: 40 mA, Start angle: 2.0 °2Θ, End angle: 35.0 °2Θ, Step size: 0.02 °2Θ , Time per step: 2.5 seconds. Characteristic XRPD angles and relative intensities are recorded in Table 1.

Table 1.

The solid-state NMR spectrum of the product (Figure 4) was recorded on a Bruker AMX360 instrument operating at 90.55 MHz: The solid was packed into a 4 mm zirconia MAS rotor fittec with a Kel-F cap and rotor spun at ca.10 kHz. The ¹³C MAS spectrum was acquired by cross- polarisation from Hartmann-Hahn matched protons (CP contact time 3 ms, repetition time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated (TPPM) composite sequence. Chemical shifts were externally referenced to the carboxylate signal of glycine at 176.4 ppm relative to TMS and were observed at: 19.3, 35.5, 43.6, 52.6, 57.9, 66.9, 113.1, 114.1, 126.6, 128.2, 128.4, 130.2, 138.9, 139.8, 143.1, 143.9, 151.8, 157.1, 172.0, 178.9 ppm.

Properties of the 7-Toluenesulfonate Hydrate 1, recorded for the product of Example 3

Solid State Stability of the 7-Toluenesulfonate Hydrate 1 The solid state stability of the hydrate was determined by storing approximately 1.0 g of the material in a glass bottle at a) 40°C / 75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayed by HPLC for final content and degradation products in both cases. a) 40°C / 75%o RH: No significant degradation observed (HPLC assay 97% initial). b) 50°C: No significant degradation observed (HPLC assay 98% initial).

Solubility of the 7-Toluenesulfonate Hydrate 1

The solubility of the hydrate was determined by adding water in aliquots from 1 to 1000 ml to approximately 100 mg of drug substance until the powder had dissolved. The visual solubility was confirmed by an HPLC assay of a saturated solution. Solubility: 0.6 mg/ml.

Tonset of the p-Toluenesulfonate Hydrate 1

The T_onset of the hydrate was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus. Melting endotherm was observed at: ^τonset (10°C/minute, sealed pan) = 120.1°C (peak observed at about 129°C) ^τonset (10°C/minute, open pan) = 148.8°C (peak observed at about 154°C)

Melting point of the 7-ToIuenesulfonate Hydrate 1 The melting point of the hydrate 1 was determined using a hot stage microscope. Melting point: 156°C

Example 6 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione 7-toluenesulfonate hydrate 2 A solution of /7-toluenesulfonic acid monohydrate (5.32 g) in acetone (15 ml) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (10.0 g) in acetone (100 ml) and water

(25 ml) and the reaction mixture was stirred and heated to reflux for 1 hour.

Diisopropylether (100 ml) was added and stirring was continued for 3 hours. The white solid was collected by filtration, washed with diisopropylether (100 ml) and dried under vaccum at 40°C for 16 hours to give 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate 2 (13.4 g) as a white crystalline solid.

Water content (Karl Fisher): 0.9% wt/wt

Example 7 5- [4- [2-(N-methyl-N-(2-py ridy l)amino)ethoxy] benzyl] thiazolidine-2,4- dione 7-toluenesulfonate hydrate 2

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione 7- toluenesulfonate hydrate (2.18 g), prepared as described in Example 3, was dried under vacuum at 50°C over phosphorus pentoxide for 75 hours to afford 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate 2 (2.1 g) as a white crystalline solid.

Water content (Karl Fisher): 0.8% wt/wt

Example 8 5-[4-[2-(N-methyI-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione 7-toluenesulfonate hydrate 2

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7- toluenesulfonate hydrate (1.02 g), prepared as described in Example 7, was dried under vacuum at 100°C over phosphorus pentoxide for 47 hours to afford 5-[4-[2-(N-methyl-N- (2 -pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate 2 (1.0 g) as a white crystalline solid. Water content (Karl Fisher): 1.52 % wt/wt

Example 9 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione 7-toluenesulfonate hydrate 2

5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7- toluenesulfonate hydrate (100 mg), prepared as described in Example 5, was dried under vacuum at 60°C for 16 hours to afford 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate 2 as a white crystalline solid.

Water content (Karl Fisher): 0.57 % wt/wt

Characterising data recorded for the product of Example 7

The infrared absorption spectrum of a mineral oil dispersion of the product was obtained using a Nicolet 710 FT-IR spectrometer at 2 cm"¹ resolution (Figure 5). Data were digitised at 1 cm^"1 intervals. Bands were observed at: 3521, 2929, 2853, 1743, 1699, 1641, 1617, 1545, 1510, 1462, 1409, 1377, 1331, 1296, 1268, 1245, 1230, 1193, 1124, 1073, 1053, 1033, 1009, 935, 890, 818, 769, 742, 718, 683, 651, 617, 607, 565, 556, 539,

505 cm^"

The infrared spectrum of the solid product was recorded using Perkin-Elmer Spectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands were observed at: 3531, 2980, 2784, 1743, 1697, 1642, 1617, 1547, 1510, 1461, 1442, 1409, 1333, 1296, 1268, 1245, 1223, 1165, 1138, 1123, 1073, 1053, 1032, 1009, 937, 921, 890, 867, 818, 767, 742, 718, 682 cm^"1.

The Raman spectrum of the product (Figure 6) was recorded using a System 2000 spectrometer, with excitation from a G/V laser quartz beamsplitter with a power output of 400 mW. Bands were observed at: 3106, 3062, 2921, 2873, 1750, 1608, 1546, 1462, 1443, 1385, 1330, 1266, 1232, 1214, 1203, 1178, 1125, 1034, 1010, 990, 936, 890, 837, 818, 802, 742, 719, 649, 637, 618, 607, 538, 496, 467, 440, 422, 402, 337, 297, 233 cm^"1.

The X-Ray Powder Diffractogram pattern of the product (Figure 7) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 40 kV, Generator current: 40 mA, Start angle: 2.0 °2Θ, End angle: 35.0 °2Θ, Step size: 0.02 °2Θ , Time per step: 2.5 seconds.Characteristic XRPD angles and relative intensities are recorded in Table 2. Table 2.

The solid-state NMR spectrum of the product (Figure 8) was recorded on a Bruker AMX360 instrument operating at 90.55 MHz: The solid was packed into a 4 mm zirconia MAS rotor fitted with a Kel-F cap and rotor spun at ca.lO kHz. The ¹³C MAS spectrum was acquired by cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3 ms, repetition time 15 s) and protons were decoupled during acquisition using a two-pulse phase modulated (TPPM) composite sequence. Chemical shifts were externally referenced to the carboxylate signal of glycine at 176.4 ppm relative to TMS and were observed at: 22.0, 36.1, 41.9, 54.2, 55.8, 68.3, 112.0, 113.5, 127.2, 130.0, 140.0, 141.0, 142.9, 144.8, 151.9, 157.4, 173.5, 177.2 ppm.

Properties of the 7-Toluenesulfonate Hydrate, recorded for the product of Example 6

Solid State Stability of the 7-ToluenesuIfonate Hydrate 2

The solid state stability of the drug substance was determined by storing approximately 1.0 g of the material in a glass bottle at a) 40°C / 75% Relative Humidity (RH), open exposure, for 1 month and b) at 50°C, closed, for 1 month. The material was assayed by HPLC for final content and degradation products in both cases. a) 40°C / 75%o RH: No significant degradation observed (HPLC assay 97% initial), b) 50°C: No significant degradation observed (HPLC assay 98% initial).

Solubility of the 7-Toluenesulfonate Hydrate 2

The solubility of the material was determined by adding water in aliquots from 1 to 1000 ml to approximately 100 mg of drug substance until the powder had dissolved. The visual solubility was confirmed by an HPLC assay of a saturated solution. Solubility: 0.6 mg/ml.

^onset of the 7-Toluenesulfonate Hydrate 2 The T_onset of the drug substance was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus. Melting endotherm was observed at: ^τonset (10°C/minute, sealed pan) = 132.4°C (peak observed at about 139°C) ^τonset (10°C/minute, open pan) = 148.5°C (peak observed at about 153°C)

Melting point of the 7-ToIuenesulfonate Hydrate 2

The melting point of the /7-Toluenesulfonate Hydrate 2 was determined using a hot stage microscope.

Melting point: 153°C

Claims

1. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2, 4-dione /7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate).

2. A compound according to claim 1, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate monohydrate.

3. A compound according to claim 1 or claim 2, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 1, characterised by: an infrared spectrum containing peaks at about 1748, 1347, 1257, 1249, 1064 cm"¹.

4. A compound according to any one of claims 1 to 3, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 1, characterised by a Raman spectrum containing peaks at about 2892, 1735, 1121, 474 cm-¹.

5. A compound according to any one of claims 1 to 4, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate, characterised by: an X-ray powder diffraction (XRPD) pattern containing peaks at about 8.4, 12.2, 20.5, 22.8, 33.6 degrees 2Θ.

6. A compound according to any one of claims 1 to 5, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 1 , characterised by: a Solid State ¹³C NMR spectrum containing peaks at about 19.3, 43.6, 52.6, 57.9, 66.9 ppm

7. A compound according to any one of claims 1 to 6, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 1 , characterised by: an infrared spectrum substantially in accordance with Figure 1.

8. A compound according to any one of claims 1 to 7, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 1 , characterised by: a Raman spectrum substantially in accordance with Figure 2.

9. A compound according to any one of claims 1 to 8, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 1 , characterised by: an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3.

10. A compound according to any one of claims 1 to 9, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 1 , characterised by: a Solid State C NMR spectrum substantially in accordance with Figure

1 1. A compound according to any one of claims 1 to 10, being 5-[4-[2-(N-methyl-N- (2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione 7-toluenesulfonate Hydrate 1 , characterised by:

(iv) a Solid State C NMR spectrum substantially in accordance with Figure 4.

12. A compound according to claim 1, being 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate hydrate containing 0.1 - 2.0% by wt. water, preferably 0.4 - 1.6% by wt. water.

13. A compound according to any one of claims 1 or 12, being 5-[4-[2-(N-methyl-N- (2 -pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 2, characterised by: an infrared spectrum containing peaks at about 1743, 1699, 1245 and 556 cm'¹.

14. A compound according to any one of claims 1, 12 or 13, being 5-[4-[2-(N-methyl- N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 2, characterised by: a Raman spectrum containing peaks at about 2873, 1750, 990, and 890 cm-¹.

15. A compound according to any one of claims 1 or 12 to 14, being 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate

Hydrate 2, characterised by: an X-ray powder diffraction (XRPD) pattern containing peaks at about 13.0, 13.9, 14.6, 16.6 and 19.5 degrees 2Θ.

16. A compound according to any one of claims 1 or 12 to 15, being 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate

Hydrate 2, characterised by: a Solid State ^l3C NMR spectrum containing peaks at about 41.9, 55.8, 68.3, 173.5 ppm.

17. A compound according to any one of claims 1 or 12 to 16, being 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 2, characterised by: an infrared spectrum substantially in accordance with Figure 5.

18. A compound according to any one of claims 1 or 12 to 17, being 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 2, characterised by: a Raman spectrum substantially in accordance with Figure 6.

19. A compound according to any one of claims 1 or 12 to 18, being 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 2, characterised by: an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7.

20. A compound according to any one of claims 1 or 12 to 19, being 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione 7-toluenesulfonate Hydrate 2, characterised by: a Solid State ¹³C NMR spectrum substantially in accordance with Figure 8

21. A compound according to any one of claims 1 or 12 to 20, being 5-[4-[2-(N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate Hydrate 2, characterised by:

(i) an infrared spectrum substantially in accordance with Figure 5; and (ii) a Raman spectrum substantially in accordance with Figure 6; and (iii) an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 2 or Figure 7; and (iv) a Solid State ¹³C NMR spectrum substantially in accordance with Figure 8.

22. A compound according to any one of claims 1 to 21, in isolated form.

23. A compound according to any one of claims 1 to 21, in substantially pure form.

24. A compound according to any one of claims 1 to 21, in crystalline form.

25. A compound according to any one of claims 1 to 21 , in a form having been processed in a manufacturing process requiring or generating heat.

26. A compound according to claim 25, or a solvate thereof, in a bulk form.

27. A compound according to claim 25 or 26, or a solvate thereof, wherein the processed form is selected from: a milled form, a heat-dried form, a hot melt processed form and a heat-sterilised form.

28. A compound according to any one of claims 25 to 26, or a solvate thereof, in a milled form.

29. A process for preparing 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione 7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate) according to claim 1, characterised in that 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione (Compound (I)) or a salt thereof is reacted with a suitable source of p- toluenesulfonate ion in the presence of water; and optionally thereafter as required: (i) forming a solvate thereof;

(ii) recovering the Toluenesulfonate Hydrate;

(iii) drying the product so obtained; and

(iii) further processing the Toluenesulfonate Hydrate in a manufacturing process requiring or generating heat.

30. A process according to claim 29 in which the obtained hydrate is subjected to vacuum drying to obtain a different hydrate form.

31. A pharmaceutical composition comprising 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate) or a non-aqueous solvate thereof, according to claim 1 , and a pharmaceutically acceptable carrier therefor.

32. A pharmaceutical composition comprising the 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate), according to claim 1 , in combination with one or more other anti-diabetic agents and optionally a pharmaceutically acceptable carrier therefor.

33. A pharmaceutical composition according to claim 20 or claim 21, wherein 5-[4-[2- (N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione /7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate), is present in an amount providing 1 , 2, 4, 8, 12, 4 to 8 or 8 to 12 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)).

34. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione /7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate

Hydrate)according to claim 1 , for use as an active therapeutic substance.

35. A compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione /7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate), for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

36. A use of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione 7-toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate), according to claim 1 , for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

37. A method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof, in a human or non-human mammal which comprises administering an effective, non-toxic, amount of5- [4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7- toluenesulfonate salt in hydrated form, (the Toluenesulfonate Hydrate), according to claim 1 , to a human or non-human mammal in need thereof.