WO2012071524A1

WO2012071524A1 - Arylsulfonate salts of fingolimod and processes for preparation thereof

Info

Publication number: WO2012071524A1
Application number: PCT/US2011/062058
Authority: WO
Inventors: Dirk Fischer; Wolfgang Albrecht
Original assignee: Ratiopharm Gmbh; Teva Pharmaceuticals Usa, Inc.
Priority date: 2010-11-24
Filing date: 2011-11-23
Publication date: 2012-05-31

Abstract

The present invention provides arylsulfonate salts of Fingolimod, their solid state forms and pharmaceutical formulations comprising them. The present invention further provides arylsulfonate salts of Fingolimod for use in the treatment of multiple sclerosis. The invention includes arylsulfonate salts of Fingolimod and solid state forms described herein for use in the preparation of Fingolimod base or other salts of Fingolimod, solid state forms of these other salts, and pharmaceutical formulation comprising them. The present invention further provides a pharmaceutical composition comprising one or more of the Fingolimod arylsulfonate salts and solid state forms of the present invention.

Description

ARYLSULFONATE SALTS OF FINGOLIMOD AND PROCESSES FOR

PREPARATION THEREOF

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of European patent application, No.

10014949.1, filed on 24 November 2010, the disclosure of which is herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to arylsulfonate salts of Fingolimod, their solid state forms and processes for preparation thereof and formulations thereof.

BACKGROUND OF THE INVENTION

Fingolimod, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-l,3-diol, of the following chemical structure :

is an immunosuppressive drug administered orally as a hydrochloride salt. Fingolimod was developed by Mitsubishi Tanabe Pharma and is, at the time of this writing, in phase III trials for the treatment of multiple sclerosis (MS) by Novartis.

Fingolimod, Fingolimod intermediates and their pharmaceutically acceptable salts, such as Fingolimod HCl, are disclosed in US 5,604,229, EP 812588, WO 2007/143081 and WO 03/097028. WO 2010/055028 disclose crystalline forms of Fingolimod HCl. However, this patent application does not provide procedures for preparing those polymorphs. WO 2010/055027 discloses several salts of Fingolimod and certain solid state forms of those salts.

WO 2010/055028 reports the conversion of Fingolimod hydrochloride modifications form I to form II takes place under thermal influence at about 40°C or less and that the conversion is thermo-reversible. Furthermore, it is known from WO 2010/055028 that Fingolimod hydrochloride is highly hygroscopic and forms at least two hydrate forms, in particular a monohydrate and a dihydrate.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Fingolimod, may give rise to a variety of polymorphs having distinct crystal structures and distinct physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), x-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these analytical techniques may be used to distinguish different polymorphic forms of a compound.

Discovering new salts and polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification. In addition, such discoveries can provide desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New salts and polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. This can also enlarge the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling

characteristics, improved dissolution profile, or improved shelf-life.

SUMMARY OF THE INVENTION

The present invention provides arylsulfonate salts of Fingolimod, their solid state forms and pharmaceutical formulations comprising thereof.

The present invention further encompasses arylsulfonate salts of Fingolimod as described in any aspect of the present invention for use in the treatment of multiple sclerosis.

The invention further encompasses the above described arylsulfonate salts of

Fingolimod and solid state forms for use in the preparation of Fingolimod base or other salts of Fingolimod, solid state forms of these other salts, and pharmaceutical formulation comprising thereof.

The present invention also provides Fingolimod arylsulfonate salts and solid state forms thereof for use for preparing pharmaceutical compositions. The present invention further provides a pharmaceutical composition comprising one or more of the Fingolimod arylsulfonate salts and solid state forms of the present invention. This pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable excipient. The present invention also provides a method of treating a person, e.g., a patient, suffering from multiple sclerosis by administering a therapeutically effective amount of a pharmaceutical composition comprising at least any one of the Fingolimod arylsulfonate salts and solid state forms of the present invention and optionally at least one pharmaceutically acceptable excipient to the patient in need thereof. The present invention also provides a method of treating a patient suffering from multiple sclerosis by administering a

pharmaceutical composition comprising a therapeutically effective amount of at least any one of the Fingolimod arylsulfonate salts and solid state forms of the present invention and optionally at least one pharmaceutically acceptable excipient to the patient in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows an X-ray powder diffraction pattern of Fingolimod tosylate form Tl

Figure 2 shows DSC thermogram of Fingolimod tosylate form Tl

Figure 3 shows an X-ray powder diffraction pattern of Fingolimod besylate form Bl

Figure 4 shows DSC thermogram of Fingolimod besylate form Bl

Figure 5 shows an X-ray powder diffraction pattern of Fingolimod HCl form I

Figure 6 shows an X-ray powder diffraction pattern of Fingolimod HCl form II

Figure 7 shows relative weight of Fingolimod HCl as a function of relative humidity (rh), as recorded during the vapor sorption experiment (50% RH→ 0 % RH→ 95% RH→ 50% RH)

Figure 8 shows relative weight of Fingolimod tosylate as a function of relative humidity (rh), as recorded during the vapor sorption experiment (50% RH→ 0 % RH→ 95% RH→ 50% RH)

Figure 9 shows relative weight of Fingolimod besylate as a function of relative humidity (rh), as recorded during the vapor sorption experiment (50% RH→ 0 % RH→ 95% RH→ 50% RH)

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to arylsulfonate salts of Fingolimod, solid state forms of these arylsulfonate salts and processes for preparation thereof and formulations thereof.

The known conversion of Fingolimod hydrochloride into its hydrates or into a different polymorphic form during processing, transport or storage is highly unfavourable, because the chemical and physical stability and the action on the patient's body become highly unpredictable. The possibility that some polymorphic transformation may occur during transport or storage leads to extensive efforts during transport or storage in order to prevent such transformations.

Different polymorphic forms often result in different crystal habits with different processabilities. A change of the polymorphic form during the formulation process can result in considerable difficulties for a stable process. Fingolimod is used in capsules, containing about 130 mg of excipients with 0.5 mg of Fingolimod. For such a small amount of active ingredient it is often problematic to achieve formulations with sufficient homogeneity or content uniformity. In particular, if the crystal habit changes during the storage prior to formulation or during the formulation process due to mechanical influences, the risk for formulations lacking sufficient content uniformity increases significantly.

Therefore, there is a strong need for pharmaceutically acceptable forms of Fingolimod without those mentioned disadvantages. In particular, such forms would have a well-defined polymorphic form, showing no significant tendency to convert into a different form under a wide range of conditions (temperature, humidity, etc.), and also would not show

hygroscopicity under a wide range of conditions. The Fingolimod salts and their solid state forms of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

Particularly, the salts of the invention may be more stable and of better quality than the free base, in particular during storage and distribution. .

The salts and the polymorphs of the present invention show stability (i.e., are stable) in storage under ambient room conditions, i.e. at about room temperature and atmospheric pressure, for a period of at least 16 months. The terms "stable" and "stability," as used herein, and unless indicated otherwise, in relation to the salts and polymorphs of the present invention refer to a measurable property of the solid form wherein less than 20% conversion of the starting compound to any other salt or solid state form of Fingolimod or Fingolimod base occurs over a period of at least 16 months at the above specified conditions, wherein conversion is measured by XRPD. In some embodiments, the conversion is less than 10%, less than 5%, less than 1%, or even less than 0.5%. In some embodiments, the conversion is l%-20%, 1%-10% or l%-5%, preferably, 0.5%-5%, and more preferably 0.5%-l%.

The salts of the present invention are also non hygroscopic, and exhibit absorption of atmospheric water in a significantly lower extent than that of the hydrochloride salt.

As used herein and unless indicated otherwise, the term non-hygroscopic in relation to Fingolimod salts of the present invention, as well as their solid state forms, refers to less than 1% (w/w) absorption of atmospheric water to the crystalline structure in the below specified conditions. The extent of absorption of atmospheric water can be measured by suitable analytical methods, for example, TGA or by vapor sorption test described herein below.

The following table shows mass loss of the different salts in a vapour sorption studies at temperature of 25°C and various conditions of relative humidity: Table 1:

Figures 7-9 shows relative weight change (%) of Fingolimod HCl, Fingolimod tosylate and Fingolimod besylate as a function of relative humidity (RH), as recorded during the vapor sorption experiment (50% RH→ 0 % RH→ 95% RH→ 50% RH). The figures demonstrate that the tosylate and besylate salts exhibit minor water adsorption, of less than 1%, and without any impact on the crystal structure upon the exposure to a high relative humidity. That is in contrast to the HCl salt, which according to WO 2010/055028 and Figure 7, demonstrates water absorption of up to about 14% and undergoes conversion of the crystalline structure.

A crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. The skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which factors are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.

As used herein, PXRD measurements were obtained using Cu Kod radiation having wavelength 1.5406.A.

A crystal form (or polymorph) may be referred to herein as "polymorphically pure" or as substantially free of any other crystalline (or polymorphic) forms. As used herein in this context, the expressions "polymorphically pure" or "substantially free of any other forms" will be understood to mean that the crystalline form contains 20% or less, 10%» or less, 5% or less, 2% or less, or 1% or less of any other forms of the subject compound as measured, for example, by PXRD. Thus, polymorphs of Fingolimod arylsulfonate salts, particularly Fingolimod tosylate and Fingolimod besylate, described herein as substantially free of any other polymorphic forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95%» (w/w), greater than 98% (w/w), or greater than 99%» (w/w) of the subject polymorphic form of Fingolimod arylsulfonate salts. Accordingly, in some embodiments of the invention, the described polymorphs of Fingolimod arylsulfonate salts, particularly Fingolimod tosylate and Fingolimod besylate, may contain from 1% to 20% (w/w), from 5% to 20%» (w/w), or from 5% to 10%» (w/w) of one or more other crystal forms. As used herein, the expression "room temperature" refers to a temperature from about 20 °C to about 30 °C. Usually, room temperature ranges from about 20°C to about 25 °C.

As used herein, the term "overnight" refers to a period of from about 15 to about 20 hours, typically from about 16 to about 20 hours.

As used herein, the expression "wet crystalline form" refers to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under a flow of nitrogen or other inert gas, etc.

As used herein, the expression "dry crystalline form" refers to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples of such conventional techniques can be, but are not limited to, evaporation, vacuum drying, oven drying, drying under a flow of nitrogen or other inert gas, etc.

As used herein, and unless stated otherwise, the term "anhydrous" in relation to crystalline Fingolimod arylsulfonate salts, particularly Fingolimod tosylate and Fingolimod Besylate, relates to a crystalline form of Fingolimod arylsulfonate salts which contains not more than 0.5% (w/w) of either water or organic solvents as measured by TGA;, or , in cases where the solvent is not water, the solvent content is between 1 ppm and 3500 ppm, preferably less than 1500 ppm, more preferably less than 500 ppm, particularly less than 200 ppm. The solvent content may be determined using an Agilent Gas Chromatograph (6890N), equipped with Gerstel® Multi Purpose Sampler MPS2.

As used herein, and unless stated otherwise, the term "hydrate", throughout the invention refers to a solid state form having water content from 0.1 to 8 wt.%, more preferably from 0.5 to 5 wt.%, still more preferably from 0.8 to 3.5 %. The water content may be determined according to the Karl Fischer method as described in Ph. Eur. 6.0, edition, 2008, section 2.5.12. The determination is preferably done using a Mettler Toledo DL31 Karl Fischer Titrator. Usually, a sample of 50 to 100 mg of the salt is analyzed.

As used herein, the term Fingolimod hydrochloride form I refers to Fingolimod hydrochloride characterized by an X-ray powder diffraction pattern with peaks at about 3.6, 7.1, 10.7, 12.5, 15.4 and 20.6 degrees 2-theta, an X-ray powder diffraction pattern as depicted in Figure 5, or a combination thereof. As used herein, the term Fingolimod hydrochloride form II refers to Fingolimod hydrochloride characterized by an X-ray powder diffraction pattern with peaks at about 3.5, 6.9, 10.4, 14.6, 19.2, 20.3 and 20.9 degrees 2-theta, an X-ray powder diffraction pattern as depicted in Figure 6, or a combination thereof.

In one embodiment, the present invention encompasses salts of Fingolimod with arylsulfonic acids (hereinafter referred to as "Fingolimod arylsulfonates").

Generally, various kinds of arylsulfonic acids can be used to produce the Fingolimod arylsulfonates of the present invention. Preferably, the Fingolimod arylsulfonates of the present invention comprise an arylsulfonate moiety of the formula (III):

(III) wherein R¹ to R⁵ are independently an organic residue. An "organic residue" should consist of C, H, O, N, S and/or halogen atoms and preferably consists of 1 to 20 of said atoms. More preferably, R¹ to R⁵ are independently hydrogen, halogen, a d to C₁₀ alkyl, a C₆ to Cio aryl or a C₆ to Cio alkaryl residue. Still more preferably R¹ to R⁵ are hydrogen or a C_\ to C₄ alkyl. Most preferably, R¹, R², R⁴ and R⁵ are hydrogen and R³ is methyl. Alternatively, most preferably, R¹ to R⁵ are hydrogen.

In a specific embodiment, the present invention encompasses Fingolimod tosylate:

Tosylate The Fingolimod tosylate salt can be isolated. Preferably, Fingolimod tosylate is present in crystalline form.

In a particular preferred embodiment, the present invention encompasses a crystalline Fingolimod tosylate salt characterised by an X-ray powder diffraction pattern having at least two, preferably at least four, and more preferably all peaks at the following 2-theta values. The peaks preferably can have (but do not necessarily have to have) the following intensities:

In a specific embodiment, the Fingolimod salt is a tosylate salt characterised by an X- ray powder diffraction pattern corresponding to that shown in Figure 1.

This crystalline Fingolimod tosylate salt can be also characterized by analytical data, such as DSC. The DSC thermogram of Fingolimod tosylate according to the present invention shows endothermic peaks at 107.4°C± 0.5°C; 139.6°C± 0.5°C and 158.7°C± 0.5°C, indicating phase transitions at temperatures far above 40 °C. Reference is made to Figure 2.

The above described crystalline Fingolimod tosylate salt is designated herein as form Tl . Form Tl can be an anhydrous form. Form Tlcan also be characterized by data selected from: an XRPD pattern having peaks at 3.5, 6.8, 10.0, 19.9 and 23.2 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 1 ; or by combinations thereof. Form Tl can be further characterized by an XRPD pattern having one or more additional pealcs selected from 16.6, 18.5, 26.5, 29.9 and 33.2 degrees two theta ± 0.2 degrees two theta. Alternatively, Form Tl can be characterized by an XRPD pattern having peaks at 3.5, 6.8, 10.0, 19.9 and 23.2 degrees two theta ± 0.2 degrees two theta and also having any one, two, three, four or five additional peaks selected from 16.6, 18.5, 26.5, 29.9 and 33.2 degrees two theta ± 0.2 degrees two theta.

Form Tl has advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

Particularly, Form Tl may be more stable and of better quality than the free base, in particular during storage and distribution. .Furthermore, form Tl is non hygroscopic, and exhibit absorption of atmospheric water in a significantly lower extent than that of the hydrochloride salt, without conversion of the crystalline structure.

In a further specific embodiment, the present invention encompasses Fingolimod besylate.

Besylate

The Fingolimod besylate salt can be isolated. Preferably the Fingolimod besylate is present in crystalline form.

In a particular preferred embodiment, the present invention encompasses Fingolimod besylate salt characterised by an X-ray powder diffraction pattern having at least two, preferably at least four, and more preferably all pealcs at the following 2-theta values. The peaks preferably can have (but do not necessarily have to have) the following intensities: Angle 2-Theta ° (± 0.2°) Relative Intensity %

3.22 100.0

6.39 1.4

9.60 3.8

16.03 0.4

19.27 5.1

25.81 1.5

39.14 1.2

In a specific embodiment, the salt is a besylate salt characterised by an X-ray powder diffraction pattern corresponding to that shown in Figure 3.

This crystalline Fingolimod tosylate salt can be also characterized by analytical data, such as DSC. The DSC thermogram of Fingolimod besylate according to the present invention shows endothermic pealcs at 76.6°C; 109.1°C and 146.1°C, indicating phase transitions at temperatures far above 40°C. Reference is made to Figure 4.

The above described crystalline Fingolimod besylate salt is designated herein as form Bl . Form Bl can be an anhydrous form.

Form Bl can also be characterized by data selected from: an XRPD pattern having peaks at 3.2, 6.4, 9.6, 19.3 and 25.8 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 3; or by combinations thereof. Form Bl can be further characterized by an XRPD pattern having one or more additional peaks at 16.0, 29.1 and 39.1 degrees two theta ± 0.2 degrees two theta. Alternatively, Form Bl can be characterized by an XRPD pattern having peaks at 3.2, 6.4, 9.6, 19.3 and 25.8 degrees two theta ± 0.2 degrees two theta and also having any one, two, or three additional pealcs selected from 16.0, 29.1 and 39.1 degrees two theta ± 0.2 degrees two theta. Form Bl has advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability - such as storage stability, stability to dehydration, stability to polymorphic conversion, low hygroscopicity, and low content of residual solvents.

Particularly, Form Bl may be more stable and of better quality than the free base, in particular during storage and distribution. .Furthermore, form Bl is non hygroscopic, and exhibit absorption of atmospheric water in a significantly lower extent than that of the hydrochloride salt, without conversion of the crystalline structure.

The present invention further relates to hydrates and solvates of Fingolimod arylsulfonates. Solvates and also hydrates of the arylsulfonate salts according to the invention may be present, for example, as hemi-, mono-, di-, tri-, tetra-, penta-, hexa-solvates or hydrates, respectively. Solvents used for crystallization, such as acetonitrile, alcohols, such as methanol, ethanol, aldehydes, ketones, such as acetone, esters, such as ethyl acetate, or alkanes, such as pentane, hexane, heptane or cyclohexane, may be incorporated in the crystal lattice. Preferably the solvent is an alcohol, especially a Ci-3 alcohol such as methanol, ethanol, n-propanol or iso-propanol. Ethanol is particularly preferred.

The above salts and solid state forms of Fingolimod arylsulfonate salts, particularly Fingolimod tosylate and Fingolimod besylate, can be used to prepare Fingolimod or other Fingolimod salts and solid state forms thereof; in particular Fingolimod hydrochloride, and/or pharmaceutical compositions containing such salts.

The present invention encompasses a process for preparing a Fingolimod salt comprising preparing any one or a combination of the Fingolimod arylsulfonate salt and solid state forms according to the present invention and converting them to said Fingolimod salt. Optionally, the resulting fingolimod salt can be subsequently formulated into a pharmaceutical composition. The conversion can comprise, for example, basifying a solution containing the Fingolimod arylsulfonate salt of any embodiment of the present invention and reacting the obtained Fingolimod base with an appropriate acid to obtain the corresponding salt. Appropriate acids include, for example, mineral acids such as hydrochloric acid sulfuric acid, phosphoric acid and nitric acid, and organic acids, such as methane sulfonic acid, ethanesulfonic acid, toluenesulfonic acid, camphor sulfonic acid, fumaric acid, tartaric acid, and maleic acid. In some embodiments, this process comprises preparing any one or a combination of Fingolimod arylsulfonate salt and solid state forms of the present invention and converting them to Fingolimod hydrochloride, for example by basifying a solution containing said Fingolimod arylsulfonate salt and reacting the obtained Fingolimod base with hydrochloric acid. Optionally, the resulting fingolimod hydrochloride can be used to prepare a pharmaceutical composition of fingolimod hydrochloride

The arylsulfonate salts and solid states of the present invention can be used to prepare pharmaceutical formulations.

The present invention further encompasses 1) a pharmaceutical composition comprising any one or combination of arylsulfonate salts and solid state forms, as described above, and at least one pharmaceutically acceptable excipient; 2) the use of any one or combination of the above-described arylsulfonate salts and solid state forms, in the manufacture of a pharmaceutical composition, 3) a method of treating a person, such as a patient, suffering from multiple sclerosis, and 4) one or a combination of solid state forms of fingolimod arylsulfonate salts (preferably fingolimod tosylate or fingolimod besylate) as described above, as a medicament, particularly for multiple sclerosis. The pharmaceutical composition can be useful for preparing a medicament. The present invention also provides arylsulfonate salts and solid state forms as described above for use as a medicament.

A further subject of the invention relates to a process for the production of salts of Fingolimod with arylsulfonic acids. It is noted that the comments made above for the arylsulfonates also apply to the process of the present invention, i.e. preferably arylsulfonic acids of the formula IV

(IV) are used, wherein R¹ to R⁵ are defined as above.

The salts of the invention can be prepared by reacting the free base of Fingolimod with an arylsulfonic acid, preferably in an equimolar amount or in a slight excess, preferably about 1 to about 1.2 mole equivalents, more preferably about 1 to about 1.1 mole equivalents and most preferably about 1.05 mole equivalents, and preferably in an appropriate solvent. Appropriate solvents can be chosen from alcohols, esters, ethers, haloalkanes, aldehydes, ketones, nitriles or mixtures thereof. Preferred solvents include methanol, ethanol, propane- 1- ol, propane-2-ol, methyl acetate, ethyl acetate, diethyl ether, tetrahydrofuran, 1,4-dioxane, methylene chloride, trichloromethane, acetone or acetonitrile. Preferably, the solvent is a Cj- C₄ alcohol, more preferably methanol, ethanol, n-propanol, or isopropanol, and more preferably methanol or ethanol. Ethanol is a particularly preferred solvent. The reaction is performed at a temperature from 0°C tol00°C. Preferably, the reaction is performed at a temperature from 20 °C to 70°C. The product of the process as described can be isolated by cooling the reaction mixture, optionally seeding the cooled solution and subsequent filtration. Alternatively, the product of the process as described can be isolated by adding an anti- solvent to the reaction mixture, optionally seeding the solution and subsequent filtration. For the completeness of the crystallisation it can be advantageous to leave the reaction mixture standing before product separation. In this process the reaction mixture can optionally be stirred. The temperature while stirring can be between -78°C and a room temperature of about 20°C. In another embodiment of the present invention, the product of the process as described can be isolated by removing some or all of the solvent or solvent mixture by distillation with optional trituration of the product after removal of the solvent.

The present invention further relates to pharmaceutical compositions comprising the above mentioned new forms of Fingolimod.

The term "pharmaceutical composition" refers to single dosage forms, such as tablets, capsules, pellets, etc., as well as powders or granules, which are used in the preparation of single dosage forms. Where it is referred to the total weight of the pharmaceutical

composition and the pharmaceutical composition in a single dosage form, the total weight is the weight of the single dosage form excluding, if applicable, the weight of any coating or capsule shell. The active pharmaceutical ingredient, i.e. the Fingolimod in its salt forms as described herein, can be present in the pharmaceutical composition in an amount of 0.01 to 10 % by weight, preferably 0.1 to 0.8 % by weight of the total weight of the composition.

Advantageous properties regarding solubility, homogeneity and flowability can be achieved when the pharmaceutical composition of the present invention has a mean particle size (D50) of 1 to 800 μπι, preferably 5 to 600 μπι, more preferably 10 to 400 μπι. The volume mean particle size (D50) can be determined by the light scattering method, using a Mastersizer 2000 apparatus made by Malvern Instruments (wet measurement, 2000 rpm, ultrasonic waves for 60 sec, data interpretation via Fraunhofer method).

A bulk density of the pharmaceutical composition ranging from 0.3 to 0.9 g/ml, preferably from 0.4 to 0.8 g/ml, is advantageous.

The pharmaceutical composition of the invention preferably possesses a Hausner factor in the range of 1.05 to 1.65, more preferably of 1.10 to 1.50. The Hausner factor is the ratio of bulk density to tapped density. Tapped and bulk density preferably are determined according to Ph.Eur. 6.0, 2.2.42.

The pharmaceutical composition of the present invention can further comprise one or more pharmaceutically acceptable excipients, such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers. As pharmaceutically acceptable excipients conventional excipients known to the person skilled in the art may be used. See for example "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", edited by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Powder X-ray Diffraction fXRD) method

XRPD samples were analyzed on a Brulcer-ASX D8 Advance powder X-Ray Diffractometer.

The measurement conditions were as follows:

Measurement: in Bragg-Brentano-Geometry on vertical goniometer (reflection,

theta-theta, 435 mm measurement circle diameter) with sample rotation (30 rpm) on 9 position sample stage

Radiation: CuKctlQ .5406 A), Tube (Siemens FLCu2K), power 38 kV/40 mA

Detector: Position sensitive detector VANTEC-1

3° capture angel (2theta)

variable antiscatter slit V6 (no divergence slit)

detector slit 10.39 mm

4° soller slit

primary beam stop (<1° 2-theta)

Monochromator: none

Second filter: Ni filter 0.1 mm (0.5%)

Start angle: 1°

End angle: 55°

Measurement time: 11 min

Step: 0.016° 2-theta

Software: EVA (Bruker-AXS, Karlsruhe)

Differential Scanning Calorimetry (DSC) method

DSC thermograms were obtained using a Mettler Toledo Model DSC 822e:

Heating range: 30 to 360°C

Heating rate: 10°C/min

Purge gas: nitrogen 50 ml/min

Sample holder: 40 μΐ aluminium crucible instrument B-545

IR method

Samples were analyzed on a Thermo Nicolet, Avatar 330 FT-IR.

HPLC/UV method

Instrument: Agilent 1200

Column: Supelco Ascentis RP Amide, 150 x 4.6 mm, 3 μπι Solvent A: 20 mM KH2P04 and 10 mM octanesulfonic acid Solvent B: acetonitrile

Flow rate : 1.0 ml/min

Detection: UV (λ=20 nm) The invention is further illustrated by the following examples, which are not intended to be limiting.

Vapor sorption experiments^')

Instrument: SPSx-1 μ (Projekt Messtechnik, Ulm, Germany)

Temperature: 25°C

Humidity cycles as presented in table 1.

EXAMPLES

Starting material:

Fingolimod can be synthesized according o the produces described in e.g. EP 0641406, Kuichi et al, J. Med Chem 2000, 43, 2946-2961, EP1129066 WO2009/115534 or US 5,604,229, Example 28 )

Example 1: Synthesis of Fingolimod Tosylate

5.00 g of Fingolimod free base (16.3 mmol) were dissolved in 100 mL hot ethanol (absolute, >99%). 3.25 g p-toluenesulfonic acid (17.1 mmol) were added to the solution in five portions (each 0.65 g). The solution was left standing at ambient temperature (about 20°C to about 22°C) for 16h. After that, the reaction mixture was cooled to -18°C and left standing for additional 24h at the same temperature, in order to complete crystallisation. The precipitated crystals were filtrated off at ambient temperature (about 20°C to about 22°C), washed with cool (about 4°C to about 6°C) ethanol (absolute, >99%) and dried at 50°C for 24h (on normal atmospheric air). .

Yield: 4.01 g (8.4 mmol)

Melting point: 156.8°C

XRPD shows characteristic signals at the following 2-theta values: 3.479°; 6.788°; 10.043°; 16.574°; 19.867°; 23.180°; 29.858°.

The IR spectrum shows characteristic absorption maxima at [cm^"1] 685.6; 818.2; 1008.2; 1032.1; 1052.0; 1065.9; 1106.6; 1122.2; 1167.8; 1180.9; 1215.4; 1279.2; 1320.7; 1379.1; 1421.5; 1466.8; 1497.5; 1605.6; 2850.5; 2918.6; 3027.2; 3070.8; 3189.5; 3258.4; 3447.9. The DSC showes endothermic peaks at 107.42°C; 137.69°C and 158.68°C.

The obtained Fingolimod tosylate form is anhydrous form

Example 2: Synthesis of Fingolimod Besylate

5.00 g Fingolimod free base (16.3 mmol) were dissolved in 100 mL hot ethanol (absolute, >99%) . To this solution were added 2.70g of benzenesulfonic acid (17.1 mmol) in five portions (each 0.54 g). The reaction mixture was allowed to cool to ambient temperature (about 20°C to about 22°C) and left standing for 16h at the same temperature. After that, the reaction mixture was cooled to -20°C and kept at that temperature for additional 24h in order to complete crystallisation. The precipitated crystals were filtrated off at ambient

temperature, washed with cool(about 4°C to about 6°C) ethanol and dried at 50°C for 24h (on normal atmospheric air).

Yield: 2.4 g (5.2 mmol)

Melting point: 144.7°C

XRPD showes characteristic signals at the following 2-theta values: 3.219°; 6.386°; 16.030°; 19.272°; 25.809°; 39.144°.

The IR spectrum showes characteristic absorption maxima at [cm^"1] 610.3; 690.9; 730.5; 753.1; 767.4; 781.1; 819.0; 830.5; 838.6; 890.9; 922.8; 995.7; 1012.9; 1032.1; 1054.9; 1069.5; 1084.1; 1122.3; 1153.9; 1203.7; 1278.2; 1311.4; 1325.8; 1342.6; 1378.8; 1397.6; 1421.5; 1444.5; 1461.7; 1514.8; 1595.5; 2851.3; 2920.9; 2952.8; 2962.2; 3017.0; 3053.4; 3141.1; 3341.1; 3410.9.

The DSC showes endothermic peaks at 76.62°C; 109.08°C and 146.07°C.

The obtained Fingolimod besylate form is anhydrous form

Further aspects and features of the present invention are set out in the following numbered embodiments:

1. Fingolimod arylsulfonate.

2. Fingolimod salt according to embodiment 1, wherein the arylsulfonate moiety has the following formula

wherein each of R¹ to R⁵ is independently an organic residue.

3. Fingolimod salt according to embodiment 1 or 2, wherein the arylsulfonate moiety is tosylate.

4. Fingolimod tosylate according to embodiment 3 in crystalline form, wherein the salt is characterised by an X-ray powder diffraction pattern having at least two, preferably at least four peaks at the following 2-theta values: 3.48 °; 6.79 °; 10.04 °; 16.57 °; 19.87 °; 23.18 °; 29.86 °.

5. Fingolimod salt according to embodiment 1 or 2, wherein the arylsulfonate moiety is besylate.

6. Fingolimod besylate according to embodiment 5 in crystalline form, wherein the salt is characterised by an X-ray powder diffraction pattern having at least two, preferably at least four peaks at the following 2-theta values: 3.22; 6.37 °; 9.60 °; 16.03 °; 19.27 °; 25.8 °; 39.14 7. Fingolimod salt according to any of the preceding embodiments in form of a hydrate and/or a solvate,

8. Fingolimod salt according to any of the preceding embodiments, wherein the salt has a water content of 0.1 to 8 wt.%.

9. Fingolimod salt according to any of the preceding embodiments, wherein the salt has a residual solvent content of 0.01 to 6 wt.%.

10. Process for producing Fingolimod arylsulfonates comprising reacting the free base of Fingolimod with an arylsulfonic acid.

11. Pharmaceutical composition comprising a Fingolimod salt according to any one of embodiments 1 to 9.

12. Pharmaceutical composition according to embodiment 11, comprising 0.01 to 10 % by weight, preferably 0.1 to 0.8 % by weight Fingolimod salt, based on the total weight of the composition.

Claims

What is claimed is:

1. Fingolimod arylsulfonate salt.

2. Fingolimod arylsulfonate salt according to claim 1, wherein the arylsulfonate moiety has the following formula

wherein each of ¾ to R5 is independently an organic residue.

3. A Fingolimod arylsulfonate salt according to claim 1 or claim 2 which is

Fingolimod tosylate.

4. Fingolimod tosylate according to Claim 3 which is crystalline, preferably wherein the Fingolimod tosylate is crystalline form Tl.

5. Fingolimod tosylate according to claim 3 or claim 4 characterised by data selected from: an X-ray powder diffraction pattern having at least two peaks, or at lease three peaks, or at least four peaks at the following 2-theta values: 3.48, 6.79, 10.04, 16.57, 19.87, 23.18 and 29.86 degrees 2-theta ± 0.2 degrees 2-theta; an X- ray powder diffraction pattern substantially as depicted in Figure 1; or combinations thereof.

6. The Fingolimod tosylate according to any one of claims 3 to 5, further

characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1.

7. Fingolimod tosylate according to claim 3 or claim 4 characterized by data selected form: an XRPD pattern having peaks at 3.5, 6.8, 10.0, 19.9 and 23.2 degrees two theta ± 0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in Figure 1 ; or combinations thereof.

8. Fingolimod tosylate according to claim 7, further characterized by an XRPD

pattern having any one, two, three, four or five additional peak selected from 16.6, 18.5, 26.5, 29.9 and 33.2 degrees two theta ± 0.2 degrees two theta.

9. A Fingolimod arylsulfonate salt according to claim 1 or claim 2 which is

Fingolimod besylate.

10. Fingolimod besylate according to Claim 9 which is crystalline and preferably wherein the Fingolimod besylate is crystalline form Bl.

11. Fingolimod besylate according to claim 9 or 10 characterised by data selected from: an X-ray powder diffraction pattern having at least two, or at least three, or at least four peaks at the following 2-theta values: 3.22, 6.37, 9.60, 16.03, 19.27, 25.8 and 39.14 degrees 2-theta ± 0.2 degrees 2-theta; an X-ray powder diffraction pattern substantially as depicted in Figure 3; or combinations thereof.

12. Fingolimod besylate according to claim 9 or 10 characterised by data selected from: an XRPD pattern having peaks at 3.2, 6.4, 9.6, 19.3 and 25.8 degrees two theta ± 0.2 degrees two theta; an X-ray powder diffraction pattern substantially as depicted in Figure 3; or combinations thereof.

13. Fingolimod besylate according to claim 12 further characterized by an XRPD

pattern having any one, two or three peaks selected from 16.0, 29.1 and

39.1 degrees two theta ± 0.2 degrees two theta.

14. Use of a Fingolimod arylsulfonate salt according to any one of the preceding

claims in the preparation of Fingolimod base or another Fingolimod salt or a solid state form thereof, or for the preparation of a pharmaceutical composition of the fingolimod salt or solid state form thereof.

15. The use according to claim 14 wherein the Fingolimod salt that is prepared is Fingolimod hydrochloride.

16. A process for preparing a Fingolimod salt comprising preparing any one or a combination of Fingolimod arylsulfonate salts according to any one of claims 1- 13 and converting them to another Fingolimod salt.

17. The process according to claim 16, wherein the process comprises

a) basifying a solution containing a Fingolimod arylsulfonate salt to produce Fingolimod base; and

b) reacting the obtained Fingolimod base with an appropriate acid to obtain the corresponding salt.

18. The process according to claim 16 or 17, wherein the Fingolimod hydrochloride salt is prepared and the acid in step b) is hydrochloric acid.

19. A process according to any one of claims 16-18, further comprising preparing a pharmaceutical composition of the fingolimod salt.

20. Fingolimod arylsulfonate salt according to any one of claims 1-13 for use in the manufacture of a pharmaceutical composition.

21. A pharmaceutical composition comprising a Fingolimod arylsulfonate salt

according to any one of claims 1-13; and at least one pharmaceutically acceptable excipient.

22. A Fingolimod arylsulfonate salt according to any one of claims 1-13 for use treating multiple sclerosis.

3. A method of treating a person suffering from multiple sclerosis, comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 21 to the person in need of the treatment.