TOLUENESULFONATE SALTS 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) (hereinafter also referred to as the "Toluenesulfonate") and discovered that the toluenesulfonate salt is particularly stable and hence is suitable for bulk preparation and handling. The novel Toluenesulfonate possesses good bulk flow properties and is a high melting crystalline material and hence is 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.
The novel salt can be prepared by an efficient and economic process particularly suited to large-scale preparation.
The novel toluenesulfonate 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 p-toluenesulfonate salt as a novel compound.
The Toluenesulfonate has been isolated with a low (e.g. 0.2% by wt.) water content, which is consistent with regarding the isolated salt as an anhydrate (1 molar equivalent of H2O = 3.3% by wt.)
Accordingly, the present invention also provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione p-toluenesulfonate anhydrate as a novel compound. In one suitable embodiment, there is provided a Toluenesulfonate characterised by
(i) an infrared spectrum containing peaks at about 1755, 1706, 1301, 1224, 1170 cm^; and/or
(ii) a Raman spectrum containing peaks at about 3054, 2927, 1302, 1260, and 602 cm-1; and/or
(iii) an X-ray powder diffraction (XRPD) pattern containing peaks at about 4.5, 4.7, 5.8, 9.2, 17.6 and 24.2 degrees 2Θ; and/or (iv) a Solid State 13C NMR spectrum containing peaks at about 50.8, 53.5, 65.0, 155.5 ppm
In one favoured aspect, the Toluenesulfonate provides an infrared spectrum substantially in accordance with Figure 1.
In one favoured aspect, the Toluenesulfonate provides a Raman spectrum substantially in accordance with Figure 2.
In one favoured aspect, the Toluenesulfonate provides an X-Ray powder diffraction pattern (XRPD) substantially in accordance with Table 1 or Figure 3.
In one favoured aspect, the Toluenesulfonate provides a Solid State 13C NMR spectrum substantially in accordance with Figure 4. In a further favoured aspect, the Toluenesulfonate provides a melting point in the range of from 160 to 175 °C, such as 163 to 170°C, for example 166.7 °C .
In a preferred aspect, the invention provides 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione toluenesulfonate, 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 13C NMR spectrum substantially in accordance with Figure 4. The present invention encompasses the Toluenesulfonate isolated in pure form or when admixed with other materials.
Thus in one aspect there is provided the Toluenesulfonate in isolated form.
In a further aspect there is provided the Toluenesulfonate in substantially pure form. In yet a further aspect there is provided the Toluenesulfonate in crystalline form.
Also, the invention provides the Toluenesulfonate or solvate thereof 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 or solvate thereof 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.
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, or a solvate thereof, in a pharmaceutically acceptable form, especially in a bulk formand 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 form or a spray dried form; for example in a form having being hot melt processed; for example in a form having being heat-sterilised by such as autoclaving.
Furthermore, the invention provides the Toluenesulfonate or solvate thereof 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, 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 of p-toluenesulfonate ion; and optionally thereafter as required:
(i) forming a solvate thereof;
(ii) recovering the Toluenesulfonate or solvate thereof ; or
(iii) further processing the Toluenesulfonate or solvate therof in a manufacturing process requiring or generating heat.
A suitable reaction solvent is an ether, for example tetrahydrofuran, or an alkanol such as propan-2-ol, a hydrocarbon, such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane or an organic acid such as acetic acid; or a mixture thereof. Conveniently, the source of p-toluenesulfonate ion is p-toluenesulfonic acid. The p-toluenesulfonic acid may be added as a solid or in solution, for example in 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 p-toluenesulfonic acid, in particular p-toluenesulfonic acid monohydrate, in tetrahydrofuran may be added to a solution of Compound (I) in the same solvent.
Typically the salt is formed under generally anhydrous conditions e.g. preferably < 1% water.
An alternative source of p-toluenesulfonate ion may be provided by a base salt of p-toluenesulfonic acid for example ammonium p-toluenesulfonate, or the p-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 p- 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 about 60°C, although any convenient temperature that provides the required product may be employed. As indicated above the Toluenesulfonate can exist as a solvate. Suitable solvates are pharmaceutically acceptable solvates, such as non-aqueous solvates
Solvates of the Toluenesulfonate may be prepared according to conventional procedures, for example by crystallising or recrystallising from a solvent which provides or contains the solvate moiety, or by exposing the Toluenesulfonate to the solvate moiety as a vapour. When the solvate is formed by crystallization methods the nature of the solvate is typically dictated by the solvent from which the Toluenesulfonate is crystallized. A Toluenesulfonate solvate, especially a non-aqeous solvate, is a favoured aspect of the invention.
Solvates of the Toluenesulfonate are prepared according to conventional procedures.
Recovery of the required compound generally comprises crystallisation from an appropriate solvent, conveniently the reaction solvent, usually assisted by cooling. For example, the Toluenesulfonate may be crystallised from an ether such as tetrahydrofuran. An improved yield of the salt can be obtained by evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the product form.
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 "Tonset" 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 in respect of certain compounds the term "good flow properties" is suitably characterised by the said compound having a Hausner ratio of less than or equal to 1.5, especially of less than or equal to 1.25. "Hausner ratio" is an art accepted term. When used herein the term 'prophylaxis of conditions associated with diabetes mellitus1 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 for use as an active therapeutic substance.
More particularly, the present invention provides the Toluenesulfonate for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.
The Toluenesulfonate may be administered er se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Suitable methods for formulating the Toluenesulfonate are generally those disclosed for Compound (I) in the above mentioned publications. Accordingly, the present invention also provides a pharmaceutical composition comprising the Toluenesulfonate and a pharmaceutically acceptable carrier therefor. The Toluenesulfonate 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 reconstirution 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, hydroxyefhylcellulose, 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 p-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 or a pharmaceutically acceptable solvate thereof 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 or a pharmaceutically acceptable solvate thereof 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 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 or a pharmaceutically acceptable solvate thereof in an amount providing up to 12mg, including l-12mg such as 2-12mg of Compound (I), especially 2-4mg, 4-8mg or 8-12mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12mg of Compound (I). Thus in particular there is provided a pharmaceutical composition comprising the Toluenesulfonate or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor, wherein the Toluenesulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 1, 2, 4, 8, 12, 4 to 8 or 8 to 12mg of Compound (I); such as lmg of Compound (I); such as 2mg of Compound (I); such as 4mg of Compound (I); such as 8mg of Compound (I); such as 12mg of Compound (I).
The invention also provides a pharmaceutical composition comprising the Toluenesulfonate or a pharmaceutically acceptable solvate thereof in combination with one or more other anti-diabetic agents and optionally a pharmaceutically acceptable carrier thereof. 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 or a pharmaceutically acceptable solvate thereof in combination with one or more other anti-diabetic agents. In a further aspect the present invention provides the use of the Toluenesulfonate or a pharmaceutically acceptable solvate thereof 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 or a pharmaceutically acceptable solvate thereof 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 or a pharmaceutically acceptable solvate thereof is present in an amount providing up to 12mg, including l-12mg, such as 2-12mg of Compound (I), especially 2-4mg, 4-8mg or 8-12mg of Compound (I), for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12mg 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 or a pharmaceutically acceptable solvate thereof is present in an amount providing lmg of Compound (I); the Toluenesulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 2mg of Compound (I); the Toluenesulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 3mg of Compound (I); the Toluenesulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 4mg of Compound (I); or the Toluenesulfonate or a pharmaceutically acceptable solvate thereof is present in an amount providing 8mg 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 a 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 ompounds of the invention.
The following examples illustrate the invention but do not limit it in any way.
Reference Preparation 1 5-[4-[2-(N-methyI-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione p-toluenesulfonate monohydrate
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 p-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 a 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione/7- toluensulfonate hydrate (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 p-toluenesulfonate hydrate.
Example 1 5-[4-[2-(N-methyl-N-(2-pyridyI)amino)ethoxy]benzyl] thiazolidine-2,4-dionep-toIuenesulfonate
A solution of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (4.0 g) in tetrahydrofuran (50 ml) was heated to 60°C andp- toluenesulfonic acid monohydrate (2.15 g) in tetrahydrofuran (6 ml) was added. The reaction mixture was stirred at 60°C for 40 minutes and then cooled to 50°C. The mixture was seeded with the product of Reference Preparation 1 and stirred for a further 20 minutes before cooling to 21°C. The product was collected by filtration and dried under vacuum over phosphorus pentoxide to give 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy] benzyl] thiazolidine-2,4-dione -toluenesulfonate (5.4 g) as a white crystalline solid.
1H-NMR (d6-DMSO): consistent with 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione p-toluenesulfonate.
Water content (Karl Fisher): 0.2% wt/wt
Example 2 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione p-toluenesulfonate
A solution ofp-toluensulfonic acid monohydrate (5.4 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 (125 ml) at 60°C. The reaction mixture was stirred for 40 minutes at 60°C, cooled to 30°C with stirring for 1 hour and then cooled to 21°C. The white solid was collected by filtration, washed with tetrahydrofuran (50 ml) and dried under vacuum at 21°C for 30 minutes to give 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione p-toluenesulfonate (15.5 g) as a white crystalline solid.
Example 3 5-[4-[2-(N-methyl-N-(2-pyridyI)amino)ethoxy]benzyl] thiazolidine-2,4-dione p-toluenesulfonate
A solution ofp-toluensulfonic acid monohydrate (3.19 g) in acetone (5 ml) was added to a stirring solution of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione(6.0 g) in acetone (90 ml) at reflux. The reaction was heated at reflux for 25 minutes, then cooled to 21°C with stirring for 45 minutes. The white solid was collected by filtration, washed with acetone (25 ml), dried under vacuum for 15.5 hours at 21°C to give 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione p-toluenesulfonate (8.6 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: 3113, 2925, 2853, 1755, 1706, 1643, 1619, 1546, 1511, 1465, 1418, 1377, 1330, 1301, 1224, 1196, 1181, 1170, 1121, 1052, 1032, 1009, 817, 772, 721, 711, 682, 570, 565 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: 3116, 3036, 2774, 1755, 1703, 1643, 1618, 1547, 1511, 1467, 1418, 1366, 1329, 1301, 1224, 1195, 1168, 1121, 1053, 1032, 1009, 997, 932, 905, 816, 770, 738, 709, 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 nm) with a power output of 400mW. Bands were observed at 3109, 3077, 3054, 2927, 2907, 1754, 1609, 1547, 1467, 1441, 1419, 1387, 1332, 1302, 1283, 1260, 1239, 1211, 1180, 1125, 1036, 1011, 984, 931, 914, 839, 820, 801, 775, 741, 711, 683, 653, 637, 619, 602, 565, 536, 470, 395, 345, 296, 233, 83 cm"'.
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 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: 21.7, 23.0, 37.2, 39.7, 40.7, 50.8, 53.5, 65.0, 111.0, 113.0, 114.7, 117.8, 126.1, 130.5, 135.3, 141.6, 143.8, 146.5, 149.7, 151.9, 155.5, 169.4, 175.0 ppm.
Properties of the -ToIuenesulfonate, recorded for the product of Example 2
Solid State Stability of thep-Toluenesulfonate The solid state stability of the salt 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% RH: No significant degradation observed (HPLC assay 98% initial). b) 50°C: No significant degradation observed (HPLC assay 98% initial).
Solubility of the -Toluenesulfonate
The solubility of the salt was determined by adding water in aliquots from 1 to 1000 ml to approximately 100 mg of the salt until the powder had dissolved. The visual solubility was confirmed by an HPLC assay of a saturated solution. Solubility: 0.8 mg/ml.
Flow Properties of thep-Toluenesulfonate
The ratio between the bulk density and the tapped bulk density (Hausner Ratio) of the salt was determined using standard methods ("Pharmaceutics - The Science of Dosage Form Design", editor M. Aulton, 1988, published by:Churchill Livingstone). Hausner Ratio: 1.1
Melting Point of thep-Toluenesulfonate
The melting point of the salt the was determined according to the method described in the U.S. Pharmacopoeia, USP 23, 1995, <741> "Melting range or temperature, Procedure for Class la", using a Buchi 545 melting point instrument. Melting Point: 166.7°C
Tonset of thep-Toluenesulfonate
The Tonset of the salt was determined by Differential Scanning Calorimetry using a Perkin-Elmer DSC7 apparatus. τonset (10°C/minute, closed pan): 161.7 °C