WO2004007485A1

WO2004007485A1 - Besylate salts

Info

Publication number: WO2004007485A1
Application number: PCT/SE2003/001208
Authority: WO
Inventors: Alan Kirschner; James Mccabe; Emyr Williams; Ingvar Ymén
Original assignee: Astrazeneca Ab
Priority date: 2002-07-15
Filing date: 2003-07-14
Publication date: 2004-01-22
Also published as: AU2003245227A1

Abstract

The present invention relates to novel crystalline forms of 6-fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide besylate salt. The present invention also relates to the use of said compounds for the treatment of depression, generalized anxiety, eating disorders, dementia, panic disorder, sleep disorders, gastrointestinal disorders, motor disorders, endocrine disorders, vasospasm, or sexual dysfunction, pharmaceutical compositions containing them and processes for obtaining them.

Description

BESYLATE SALTS

FIELD OF THE INVENTION

[0001] The present invention relates to novel crystalline forms of 6-fluoro-8-(4-methyl- piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]- amide besylate salt, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy.

BACKGROUND

[0002] Serotonin (5-HT) is implicated in many psychiatric disorders including, but not limited to, depression, generalized anxiety, eating disorders, dementia, panic disorder, and sleep disorders. Serotonin is also implicated in gastrointestinal disorders, cardiovascular regulation, motor disorders, endocrine disorders, vasospasm and sexual dysfunction. Serotonin receptors are subdivided into at least 14 subtypes, see Barnes & Sharp, 1999, Neuropharmacology, 38: 1083-1 152, which is incorporated herein by reference. These various subtypes are responsible for serotonin's action in many pathophysiological conditions. [0003] The 5-HT) family of receptors has high affinity for serotonin and consists of five related receptors, including the 5-HT_IB and 5-HT_{I D} receptor subtypes. Compounds that interact with the 5-HT] family are known to have therapeutic potential in the above mentioned disorders and diseases. In particular, compounds that are 5HT_IB and 5HT_JD antagonist are known to be antidepressant and anxiolytic agents. Compounds that are 5HT_{I B} and 5HTj_D agonists have been used in the treatment of migraine.

[0004] The compound 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide is a 5-HT_{J B} receptor antagonist and is described in U.S. Patent Application No. 10/051 ,776, filed January 16, 2002, the subject matter of which is incorporated herein in its entirety by reference.

[0005] In the formulation of drug compositions, it is important for the active pharmaceutical ingredient (API) to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations (e.g., oral dosage forms such as tablets) comprising the active pharmaceutical ingredient.

[0006] Further, in the manufacture of oral drug compositions, it is important that a reliable, reproducible and constant plasma concentration profile of the active pharmaceutical ingredient is provided following administration to a patient.

[0007] Chemical stability, solid state stability, and "shelf life" of the active pharmaceutical ingredient are also very important factors. The active pharmaceutical ingredient, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics

(e.g., chemical composition, density, hygroscopicity and solubility) of the active pharmaceutical ingredient.

[0008] Amorphous materials are typically more difficult to handle and to formulate, provide unreliable dissolution, and are often unstable. Thus, in the manufacture of commercially viable and pharmaceutically-acceptable drug compositions, it is desirable to provide the active pharmaceutical ingredient in a substantially crystalline and stable form.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 is an X-ray powder diffractogram of Compound I besylate salt form I. [0010] Figure 2 is an X-ray powder diffractogram of Compound I besylate salt form II. [0011] Figure 3 is an X-ray powder diffractogram of Compound I besylate salt form III. [0012] Figure 4 is an X-ray powder diffractogram of Compound I besylate salt form IV. [0013] Figure 5 is an X-ray powder diffractogram of Compound I besylate salt form V.

DETAILED DESCRIPTION

[0014] The present invention provides crystalline forms of 6-fluoro-8-(4-methyl-piperazin-l-yl)- 4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide besylate salt. 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-pheny]]-amide, hereinafter referred to as Compound I, has the following structure:

[0015] Compound I is a 5-HT_{J B} ligand, capable of acting as an antagonist at 5-HT_{I B} receptors.

A process for the synthesis of Compound I is described in Example 72 of U.S. Patent

Application No. 10/051 ,776, which is incorporated herein by reference.

[0016] We have surprisingly found that Compound I besylate salt can exist in more than one crystal form. We have also found that crystalline forms of Compound I besylate salt exhibit properties such as convenient handling and chemical and solid-state stability. Crystalline forms of Compound I besylate salt are referred to herein as "forms." Numeric designations provided herein for crystalline forms of Compound I besylate salt are arbitrary and do not refer to relative thermodynamic stability or any other characteristic.

[0017] Various definitions are made throughout this document. Most words have the meaning that would be attributed to those words by one skilled in the art. Words specifically defined either below or elsewhere in this document have the meaning provided in the context of the present invention as a whole and as typically understood by those skilled in the art.

[0018] One aspect of the present invention provides Compound I besylate salt, in substantially crystalline form.

[0019] As used herein, the term "substantially crystalline" means at least about 50% crystalline and ranging up to about 100% crystalline. The present invention provides Compound I besylate salt that is at least about 50% crystalline, at least about 60% crystalline, at least about 70% crystalline, at least about 80% crystalline, at least about 90% crystalline, at least about 95% crystalline, at least about 98% crystalline, or at least about 100% crystalline in form.

[0020] The degree or percentage of crystallinity may be determined by the skilled person using

X-ray powder diffraction (XRPD). Other techniques, such as solid-state nuclear magnetic resonance (NMR), FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.

[0021] Crystalline forms of Compound I besylate salt (i.e., the compounds of the invention) may be in the form of a solvate, including but not limited to a hydrate (e.g., a monohydrate), or otherwise (e.g., in the form of an anhydrate). In some embodiments of the invention, the crystalline form of Compound I besylate salt is in the form of an anhydrate. In some embodiments of the invention, the crystalline form of Compound I besylate salt is in the form of a hydrate.

[0022] We have found that the compounds of the invention have improved stability over 6- fluoro-8-(4-methyl-piperazin- 1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl- piperazin-l-yl)-phenyl]-amide prepared described in U.S. Patent Application No. 10/051 ,776. [0023] According to a further aspect of the invention, there are provided stable forms of Compound I besylate salt.

[0024] As used herein, the terms "stable" or "stability" include chemical stability and solid-state stability. The term "chemical stability" means that the compound can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g., in an oral dosage form, such as tablet, capsule, etc.), under normal storage conditions, with little or no chemical degradation or decomposition. "Solid-state stability" means that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g., in an oral dosage form, such as tablet, capsule, etc.), under normal storage conditions, with little or no solid-state transformation (e.g., crystallization, recrystallization, solid-state phase transition, hydration, dehydration, solvatization or desolvatization). [0025] Examples of "normal storage conditions" include temperatures ranging from about minus

80 °C to about plus 50 °C, from about 0 °C to about plus 40 °C, and from 15 °C to about 30 °C; pressures ranging from about 0.1 bars to about 2 bars, more particularly at about atmospheric pressure; relative humidities ranging from about 5% to about 95%, more particularly from about 10% to about 75%; and/or exposure to 460 lux of UV/visible light for prolonged periods, for example, at least about 6 months.

[0026] According to one aspect of the present invention, there is provided 6-fluoro-8-(4-methyl- piperazin- 1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)-phenyl]- amide (Compound I) besylate salt form I.

[0027] Compound I besylate salt form I, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 1 , and exhibiting substantially the following 2-theta values and relative intensities:

[0028] The peaks, identified from the 2-theta values, have been extracted from the diffractogram for Compound I besylate salt form I. The following definitions were used to compare relative intensities, which were derived from the diffractogram measured with fixed slits:

[0029] The above definitions are also used when identifying the diffractogram peaks for other crystalline forms of Compound I besylate salt described herein.

[0030] Compound I besylate salt form I is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.

[0031] According to another aspect of the present invention, there is provided 6-fluoro-8-(4- methyl-piperazin- 1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)- phenyl]-amide (Compound I) besylate salt form II.

[0032] Compound I besylate salt form II, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 2, and exhibiting substantially the following 2-theta values and relative intensities:

[0033] Compound I besylate salt form II is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.

[0034] According to another aspect of the present invention, there is provided 6-fluoro-8-(4- methyl-piperazin- 1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -yl)- phenyl]-amide (Compound I) besylate salt form III.

[0035] Compound I besylate salt form HI, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 3, and exhibiting substantially the following 2-theta values and relative intensities:

[0036] Compound I form III is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.

[0037] According to another aspect of the present invention, there is provided 6-fluoro-8-(4- methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)- phenyl]-amide (Compound I) besylate salt form IV.

[0038] Compound I besylate salt form IV, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 4, and exhibiting substantially the following 2-theta values and relative intensities:

[0039] Compound I form IV is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.

[0040] According to another aspect of the present invention, there is provided 6-fluoro-8-(4- methyl-piperazin- 1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin- 1 -y])- phenyl]-amide (Compound I) besylate salt form V.

[0041] Compound I besylate salt form V, according to the present invention, is characterized in providing an X-ray powder diffraction pattern, as shown in Figure 5, and exhibiting substantially the following 2-theta values and relative intensities:

[0042] Compound I form V is a crystalline form exhibiting advantageous properties, such as convenient handling, chemical stability and solid-state stability.

[0043]

[0044] The compounds of the present invention may be obtained by crystallizing Compound I besylate salt.

[0045] According to a further aspect of the invention, there are provided processes for the preparation of compounds of the invention which comprise crystallizing Compound I besylate salt.

[0046] 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4- propionyl-piperazin-l-yl)-phenyl]-amide (Compound I) besylate salt may be crystallized in the presence of an appropriate solvent system or may be crystallized in the absence of a solvent

(e.g., crystallization may be from a melt, under supercritical conditions, or achieved by sublimation).

[0047] Where a solvent system is used for crystallization, a suitable solvent system may be heterogeneous or homogeneous and may thus comprise one or more solvents. Examples of appropriate solvents include, but are not limited to alkyl acetates (e.g., linear or branched Cι- alkyl acetates, such as ethyl acetate, isopropyl acetate, butyl acetate and n-butyl acetate), lower

(e.g., linear or branched Cι_-6) alkyl alcohols (e.g., methanol, ethanol, iso-propanol), aliphatic hydrocarbons (e.g., iso-octane, n-heptane) and aromatic hydrocarbons (e.g., toluene), dialkyl ketones (e.g., acetone, methyl iso-butyl ketone), acetonitrile, dichloromethane (methylene chloride), dimethylsulfoxide, tetrahydrofuran, dialkyl ethers (e.g., di-isopropyl ether), amides

(e.g., N,N-dimethylformamide), and water.

[0048] Crystallization of compounds of the present invention from a suitable solvent system, containing at least one solvent, may be achieved by attaining supers aturati on in a solvent system, by solvent evaporation, by temperature decrease, and/or via the addition of anti-solvent (i.e., a solvent in which the compounds of the invention are poorly soluble).

[0049] Crystallization temperatures and crystallization times will depend upon the concentration of the compound in solution, and upon the solvent system used.

[0050] Crystallization may also be initiated and/or effected with or without seeding with crystals of the appropriate crystalline compound of the invention, and/or by adjustment of pH.

[0051] Crystallization of compounds of the present invention can be achieved starting from pure

6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl- piperazin-l-yl)-phenyl]-amide (Compound I) besylate salt of any form, or mixtures of any form.

[0052] Compounds of the invention may be prepared in the form of solvates, hydrates, and anhydrates.

[0053] Whether an anhydrate or a solvate crystallizes is related to the kinetics and equilibrium conditions of the respective forms at the specific conditions. As will be appreciated by those skilled in the art, the crystalline form that is obtained depends upon both the kinetics and the thermodynamics of the crystallization process. Under certain thermodynamic conditions (e.g., solvent system, temperature, pressure and concentration of compound of the invention), one crystalline form may be more stable than another (or indeed any other).

[0054] Crystalline forms that have a relatively low thermodynamic stability may be kinetically favored. Therefore, kinetic factors such as time, impurity profile, agitation, the presence or absence of seeds, etc., may influence which form crystallizes. One of skill in the art may, therefore, adapt the procedures discussed herein in order to obtain different crystalline forms.

[0055] A further aspect of the present invention is to provide processes for the preparation of 6- fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl- piperazin-l-yl)-phenyl]-amide (Compound I) besylate salt forms I, II, III, IV, and V.

[0056] Compound I besylate salt form I can be obtained upon crystallization from tetrahydrofuran and water.

[0057] Compound I besylate salt form II can be obtained upon crystallization from dimethysulfoxide and ethanol.

[0058] Compound I besylate salt form III can be obtained upon crystallization from methanol. [0059] Compound I besylate salt form IV can be obtained upon recrystallization of Compound I besylate salt form III from acetonitrile.

[0060] Compound I besylate salt form V can be obtained upon recrystallization of Compound I besylate salt form II from acetonitrile.

[0061] The preparation and characterization of different forms of the compounds of the invention are described hereinafter. Different crystalline forms of the compounds of the invention may be readily characterized using, for example, X-ray powder diffraction (XRPD) methods or Raman spectroscopy.

[0062] Each of 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-

(4-propionyl-piperazin-l-yl)-phenyl]-amide besylate salt forms I, II, LTI, IV, and V, obtained according to the present invention, are substantially free from other crystal and non-crystal forms of 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl- piperazin-l-yl)-phenyl]-amide besylate salt. The phrase "substantially free from other crystal and non-crystal forms" as used herein, means that the desired crystal form of 6-fluoro-8-(4- methyl-piperazin- 1 -yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l -yl)- phenyl]-amide besylate salt, prepared according to the present invention, contains less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5% or about 0% of any other crystal and non-crystal forms of 6-fluoro-8-(4-methyl-piperazin-l-yl)-4-oxo-4H- chromene-2-carboxylic acid [4-(4-propionyl-piperazin-l-yl)-phenyl]-amide besylate salt.

[0063] One method to ensure that a particular crystalline form is prepared in the absence of other crystalline forms, is to carry out crystallization by seeding with nuclei and/or seed crystals of the desired crystalline form in the complete absence of nuclei and/or seed crystals of other crystalline forms.

[0064] Compounds of the invention may be isolated using any of a variety of techniques well known to those of skill in the art, including, but not limited to, decanting, filtering, or centrifuging.

[0065] According to another aspect of the present invention, there are provided pharmaceutical compositions comprising the compounds of the invention. A pharmaceutical composition of the invention may comprise a compound of the invention in admixture with at least one pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, and optionally other therapeutic ingredients.

[0066] The compounds of the invention may be further processed before formulation into a suitable pharmaceutical composition. For example, the crystalline form may be milled or ground into smaller particles. [0067] According to another aspect of the present invention, there is provided the use in therapy of any of the compounds of the invention.

[0068] According to another aspect of the present invention, there is provided the use of any of the compounds of the invention in the manufacture of a medicament for use in the treatment of depression, generalized anxiety, eating disorders, dementia, panic disorders, sleep disorders, gastrointestinal disorders, motor disorders, endocrine disorders, vasospasm, or sexual dysfunction.

[0069] According to a further aspect of the present invention, there is provided a method of treatment of a human or animal suffering from depression, generalized anxiety, eating disorders, dementia, panic disorder, sleep disorders, gastrointestinal disorders, motor disorders, endocrine disorders, vasospasm, or sexual dysfunction, comprising administering to the human or animal an effective amount of any of the compounds of the invention.

[0070] As used herein, the terms "treating" or "treatment" includes therapeutic treatment, as well as prophylaxis of a disease or condition. Additionally, "treating" or "treatment" refers to the amelioration and/or elimination of a disease or condition.

[0071] In accordance with this aspect of the invention, the compounds of the present invention may be administered and used as described in U.S. Patent Application 10/051,776.

[0072] The compounds of the invention have the advantage that they are in a form that provides for improved ease of handling. Further, the compounds of the invention have the advantage that they may be produced in forms that have improved chemical and solid-state stability as well as lower hygroscopicity. Thus, the compounds may be stable when stored over prolonged periods.

[0073] The invention is further illustrated by way of the following examples, which are intended to elaborate several embodiments of the invention. These examples are not intended to, nor are they to be construed to, limit the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the present invention are possible in view of the teachings herein and, therefore, are within the scope of the invention.

EXAMPLES

Example 1. Experimental procedures.

Standard X-ray diffraction measurement conditions

[0074] X-ray powder diffraction analyses (XRPD) were performed on samples prepared according to standard methods (see for example Giacovazzo et al., eds., Fundamentals of Crystallography, Oxford University Press (1992); Jenkins & Snyder, eds., Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York (1996); Bunn, ed., Chemical Crystallography, Clarendon Press, London (1948); and Klug & Alexander eds., X-ray Diffraction Procedures, John Wiley & Sons, New York (1974), each of which is incorporated herein by reference). X-ray analyses were performed using a Siemens D5000 diffractometer. [0075] Sample preparation for D5000: -30 mg material, silicon wafers. Samples were spun at 30 rpm to improve counting statistics. X-rays were generated by a: 'copper long-fine focus tube' operated at 40 kV and 40 mA, wavelength of X-rays - 1.54 A. The data for each sample were obtained using the standard scintillation detector. The collimated X-ray source was passed through an Automatic Variable Divergence Slit set at V20 (20mm path-length) and the reflected radiation directed through a 2 mm anti-scatter slit and a 0.2mm detector slit. Each sample was exposed for 1 second per 0.02° 2Θ increment (continuous scan mode) over the range 2° to 40° 2Θ in theta-theta mode. The running time for each sample was thus 31 minutes 41 seconds. The secondary soller slit was left in position.

[0076] A Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac+ version was used for control and data capture. The following definitions were used to compare relative intensities:

% Relative Intensity^* Definition

25 - 100 vs (very strong)

10 - 25 s (strong)

3 - 10 m (medium)

1 - 3 w (weak)

* The relative intensities were derived from diffractograms measured with fixed slits. Differential scanning calorimetry (DSC)

[0077] Samples were analyzed using a Mettler Toledo 822e with a heating rate of 10 °C/minute.

Example 2. Compound I Besylate Form I.

[0078] A mixture of Compound I free base (378 mg), 90% benzenesulphonic acid (122 mg), tetrahydrofuran (30 ml) and water (2 ml) was heated at 70 °C to give a clear solution. The solution was cooled to 23 °C and stirred overnight. The solid was filtered off, washed with tetrahydrofuran (2 ml)] and dried overnight in vacuo at 65 °C. The yield of Compound I besylate was 378 mg.

[0079] The crystals were analysed by XRPD. The diffractogram is shown in Figure 1 and the data are tabulated below:

Angle 2-Theta ° Intensity % Relative Intensity 7.4 100.0 vs

16.0 34.2 vs

14.7 26.4 vs

6.6 17.4 s

22.8 16.7 s

25.8 1 1.3 s

18.3 10.3 s

22.1 9.3 m

20.1 9.3 m

27.0 8.8 m

23.1 8.8 m

24.0 8.2 m

21.1 7.6 m

26.3 7.0 m

19.8 6.9 m

Example 3. Compound I Besylate Form II.

[0080] A mixture of Compound I free base (378 mg), 90% benzenesulphonic acid acid (123 mg), dimethylsulfoxide (2 ml) and ethanol (10 ml) was heated at 80 °C to give a clear solution. The solution was cooled to room temperature, diluted with more ethanol (5 ml) and the solvent allowed to evaporate over 3 days. The residual gum was stirred with ethanol (6 ml) for two days at room temperature. The solid was filtered off, washed with ethanol (2 ml) then dried overnight to a constant weight. The yield of Compound I besylate was 351 mg. Η NMR (400 MHz, CDC1₃) ,57.90 (d, 2H, J₀=9.3Hz, 2.6 anilide). 57.84 (d, 2H, J_o=8.0Hz, ArH ), 57.72 (d, 2H, J₀=9.2Hz, 3.5 anilide). 57.62 (d of d, IH, J_m=2.9Hz,

57.69 (t, IH, J₀=7.3Hz, ArH₄), 57.51 (t, 2H, J₀=7.3 Hz, ArH^.s), 57.41 (s, IH, Hj), 57.30 (d of d, IH, J_m=2.9Hz, J_FH=8.9Hz_!_H_7or5), 53.3-4.3 (br m, 16H, -NCH₂ CH₂ CH,N-) 53.08 (bd, 3H, J = 3.7Hz, NH⁺CU₃), 52.59 (q, 2H, J=7.5 Hz, COCH₂CH₃), 51.24 (t, 3H, J=7.7 Hz, COCH₂ CH₃). [0081] The crystals were analysed by XRPD. The diffractogram is shown in Figure 2 and the results are tabulated below:

Angle 2-Theta ° Intensity R Ree lative Intensity

6.6 100.0 vs

12.1 32.8 vs

15.2 32.5 vs

19.7 21.1 s

23.3 19.4 s

25.4 19.1 s 25.8 18.7 s

8.5 17.1 s

25.1 15.8 s

17.3 15.6 s

28.4 12.9 s

8.1 12.8 s

13.0 12.1 s

16.2 10.4 s

23.5 10.2 s

Example 4. Compound I Besylate Form III.

[0082] A mixture of Compound I free base (378 mg), 90% benzenesulphonic acid (122 mg) and methanol (5 ml) was heated at 50 °C to give a clear solution. The solution was cooled and stirred overnight at room temperature. The solid was filtered off, washed with methanol (2 ml) and dried overnight in vacuo at 65 °C. The yield of Compound I besylate was 260 mg. [0083] The crystals were analysed by XRPD. The diffractogram is shown in Figure 3 and the data are tabulated below:

Angle 2-Theta ° Intensity % Relative Intensity

15.5 100.0 vs

22.1 83.6 vs

7.7 82.9 vs

23.8 80.2 vs

25.9 67.2 vs

1 1.9 64.2 vs

12.5 61.8 vs

22.5 61.1 vs

20.2 55.6 vs

1 1.3 52.2 vs

23.5 49.8 vs

18.0 49.1 vs

22.8 40.6 vs

19.4 38.9 vs

24.2 36.9 vs

Example 5. Compound I Besylate Form IV.

[0084] A mixture of Compound I besylate (Form III) (lOOmg) and acetonitrile (1 ml) was stirred overnight at room temperature. The solid was collected by filtration and washed with acetonitrile (0.5ml). The yield of Compound I besylate was 94 mg. [0085] The crystals were analysed by . ^' XRPD. The diffractogram is shown in Figure 4 and the data are tabulated below:

Angle 2-Theta ° Intensity % Relative Intensity

6.0 100.0 vs

16.5 37.4 vs

12.4 35.8 vs

24.4 34.9 vs

16.0 33.6 vs

19.8 28.9 vs

3.2 28.3 vs

22.7 26.1 vs

12.1 25.8 vs

10.7 24.8 s

23.9 22.6 s

14.8 22.6 s

23.2 22.6 s

22.3 22.3 s

26.1 21.4 s

Example 6. Compound I Besylate Form V.

[0086] A mixture of Compound I besylate (Form II) (lOOmg) and acetonitrile (1 ml) was stirred overnight at room temperature. The solid was collected by filtration and washed with acetonitrile (0.5 ml). The yield of Compound I besylate was 92 mg.

[0087] The crystals were analysed by XRPD. The diffractogram is shown in Figure 5 and the data are tabulated below:

Angle 2-Theta ° Intensity % R Re< lative Intensity

5.1 100.0 vs

8.0 91.3 vs

26.0 36.5 vs

16.2 26.3 vs

19.2 26.1 vs

21.0 24.6 s

14.4 19.9 s

16.7 17.6 s

24.0 17.5 s

22.9 16.2 s

20.4 15.9 s

12.2 15.0 s 19.0 13.0 s

18.0 1 1.7 s

27.8 1 1.4 s

[0088] The foregoing examples are meant to illustrate the invention and are not to be construed to limit the invention in any way. Those skilled in the art will recognize modifications that are within the spirit and scope of the invention. [0089] AU references cited herein are hereby incorporated by reference in their entirety.

Claims

What is claimed is:

1. Compound I

besylate salt in substantially crystalline form.

2. The compound of claim 1, characterized by an X-ray powder diffraction pattern exhibiting substantially the following 2-theta values: Angle 2-Theta ° Relative Intensity

7.4 vs

16.0 vs

14.7 vs

6.6 s

22.8 s

25.8 s

18.3 s

22.1 m

20.1 m

27.0 m

23.1 m

24.0 m

21.1 m

26.3 m

19.8 m.

3. The compound of claim 1 , characterized by an X-ray powder diffraction pattern exhibiting substantially the following 2-theta values:

Angle 2-Theta ° Relative Intensity

6.6 vs

12.1 vs

15.2 vs

19.7 s

23.3 s

25.4 s

25.8 s

8.5 s

25.1 s

17.3 s

28.4 s

8.1 s

13.0 s

16.2 s

23.5 s.

4. The compound of claim 1 , characterized by an X-ray powder diffraction pattern exhibiting substantially the following 2-theta values: Angle 2-Theta ° Relative Intensity

15.5 vs

22.1 vs

7.7 vs

23.8 vs

25.9 vs

11.9 vs

12.5 vs

22.5 vs

20.2 vs

1 1.3 vs

23.5 vs

18.0 vs

22.8 vs

19.4 vs

24.2 . vs.

5. The compound of claim 1, characterized by an X-ray powder diffraction pattern exhibiting substantially the following 2-theta values:

Angle 2-Theta ^c Relative Intensity

6.0 vs

16.5 vs

12.4 vs

24.4 vs

16.0 vs

19.8 vs

3.2 vs

22.7 vs

12.1 vs

10.7 s

23.9 s

14.8 s

23.2 s

22.3 s

26.1 s.

6. The compound of claim 1, characterized by an X-ray powder diffraction pattern exhibiting substantially the following 2-theta values:

Angle 2-Theta ° Relative Intensity

5.1 vs

8.0 vs

26.0 vs

16.2 vs

19.2 vs

21.0 s

14.4 s

16.7 s

24.0 s

22.9 s

20.4 s

12.2 s

19.0 s

18.0 s

27.8 s.

A process comprising: a) forming of a crystalline form of compound I

b) isolating said crystalline form of compound I.

8. The process of claim 7, wherein step a) is achieved by crystallizing compound I from a solvent.

9. The process of claim 8, wherein said solvent is selected from the group consisting of methanol, ethanol, water, n-butyl acetate, acetonitrile, dichloromethane, dimethylsulfoxide, tetrahydrofuran, and any mixture thereof.

10. The process of claim 8, wherein seeds are added to the solvent to induce crystallization.

1 1. The process of claim 7, further comprising adding a pharmaceutically-acceptable acid to compound I before carrying out steps a) and b).

12. The process of claim 1 1, wherein the pharmaceutically acceptable acid is benzenesulfonic acid.

13. A process for the preparation of compound I besylate salt as defined in claim 2 comprising the steps of: a) dissolving or suspending compound I besylate salt of any form, or a mixture of any form in tetrahydrofuran and water; b) crystallizing the solution or suspension; and c) isolating the crystallized compound I besylate salt.

14. A process for the preparation of compound I besylate salt as defined in claim 3 comprising the steps of: a) dissolving or suspending compound I besylate salt of any form, or a mixture of any form in ethanol; b) crystallizing the solution or suspension; and c) isolating the crystallized compound I besylate salt.

15. A process for the preparation of compound I besylate salt as defined in claim 4 comprising the steps of: a) dissolving or suspending compound I besylate salt of any form, or a mixture of any form in methanol; b) crystallizing the solution or suspension; and c) isolating the crystallized compound I besylate salt.

16. A process for the preparation of compound I besylate salt as defined in claim 5 comprising the steps of: a) dissolving or suspending compound I besylate salt of any form, or a mixture of any form in acetonitrile; b) crystallizing the solution or suspension; and c) isolating the crystallized compound I besylate salt.

17. A process for the preparation of compound I besylate salt as defined in claim 6 comprising the steps of: a) dissolving or suspending compound I besylate salt of any form, or a mixture of any form in acetonitrile; b) crystallizing the solution or suspension; and c) isolating the crystallized compound I besylate salt.

18. A crystalline form of compound I prepared according to the process of any of claims 7 - 17.

19. A pharmaceutical composition comprising the compound of claim 1 in admixture with at least one pharmaceutically acceptable excipient.

20. The use of the compound of claim 1 in therapy.

21. The use of the compound of claim 1 in the manufacture of a medicament for use in the treatment of depression, generalized anxiety, eating disorders, dementia, panic disorders, sleep disorders, gastrointestinal disorders, motor disorders, endocrine disorders, vasospasm, or sexual dysfunction.

22. A method of treatment of a human or animal suffering from depression, generalized anxiety, eating disorders, dementia, panic disorder, sleep disorders, gastrointestinal disorders, motor disorders, endocrine disorders, vasospasm, or sexual dysfunction, comprising administering to the human or animal an effective amount of the compound of claim 1.