Amorphous Solid Dispersions

Abstract

The present invention relates to solid dispersions of an amorphous compound of formula (I) and a polymer matrix, processes for their preparation, and their use in therapy. [Formula 1] JPEG2023553457000010.jpg4357

Description

[Technical Field]

[0001] The present invention relates to a solid dispersion of amorphous 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone.

[0002] The present invention also relates to methods for preparing these amorphous solid dispersions and to pharmaceutical compositions containing such dispersions. [Background technology]

[0003] International Patent Application No. PCT / EP2020 / 068183, published as WO 2021 / 001288, discloses 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I): [ka] The compounds act as D1 positive allosteric modulators and are therefore useful as pharmaceuticals for treating diseases in which the D1 receptor plays a role.

[0004] International Patent Application No. PCT / EP2020 / 068183, published as WO 2021 / 001288, further discloses that the compounds of formula (I) may be useful for the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, anorexia, traumatic spinal cord injury or neuropathic pain.

[0005] It is therefore desirable to develop formulations of compounds of formula (I) suitable for administration to patients suffering from any one of the above diseases.

[0006] In particular, Example 2.8 of International Patent Application No. PCT / EP2020 / 068183, published as WO 2021 / 001288, discloses, inter alia, a monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone.

[0007] This monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone has limited solubility, which may make it difficult to formulate and / or result in low bioavailability if oral administration is desired.

[0008] There is therefore a need to improve the solubility of the monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone so that it can be incorporated into pharmaceutical compositions, particularly for oral administration. Summary of the Invention

[0009] The present invention provides an amorphous solid dispersion of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I). [ka]

[0010] In another aspect, the present invention provides a process for preparing an amorphous solid dispersion of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I).

[0011] In a further aspect, the present invention provides a pharmaceutical composition comprising an amorphous solid dispersion of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I).

[0012] In a still further aspect, the present invention provides such an amorphous solid dispersion of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I) or a pharmaceutical composition thereof for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, amotivation, traumatic spinal cord injury or neuropathic pain. [Brief explanation of the drawings]

[0013] [Figure 1] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD1, which is further described in Example 3.1. [Figure 2] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD2, which is further described in Example 3.1. [Figure 3] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD3, which is further described in Example 3.1. [Figure 4] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD4, which is further described in Example 3.1. [Figure 5] 1 shows the X-ray powder diffraction pattern of the amorphous solid dispersion ASD1 described in Example 3 after 12 months at room temperature. [Figure 6] 1 shows the X-ray powder diffraction patterns of amorphous solid dispersions ASD2, ASD3, and ASD4 described in Example 3 after 10 months at room temperature. [Figure 7] 1 depicts the dissolution profile over time of the compound of formula (I) in amorphous solid dispersion ASD1, further described in Example 5. [Figure 8] FIG. 1 shows the dissolution profile over time of the monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (compound of Formula (Ia)), which is further described in Example 5. [Figure 9] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD5, which is further described in Example 3.2. [Figure 10] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD6, which is further described in Example 3.2. [Figure 11] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD7, which is further described in Example 3.2. [Figure 12] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD8, which is further described in Example 3.2. [Figure 13] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD9, which is further described in Example 3.2. [Figure 14] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD10, which is further described in Example 3.2. [Figure 15]3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD11, which is further described in Example 3.2. [Figure 16] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD12, which is further described in Example 3.2. [Figure 17] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD13, which is further described in Example 3.2. [Figure 18] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD14, which is further described in Example 3.2. [Figure 19] FIG. 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD15, which is further described in Example 3.2. [Figure 20] 6 shows the bioavailability of the compound of formula (I) as a function of the administered dose of a suspension of ASD1 prepared according to Example 6.1. [Figure 21] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD16, which is further described in Example 3.2. [Figure 22] 3 shows the X-ray powder diffraction pattern of amorphous solid dispersion ASD17, which is further described in Example 3.2. [Figure 23] 7 depicts the dissolution profile over time of tablet A for the compound of formula (I), as further described in Example 7.2. [Figure 24] 7 depicts the dissolution profile over time of tablet B for the compound of formula (I), as further described in Example 7.2. [Figure 25] 7 depicts the dissolution profile over time of tablet C for the compound of formula (I), as further described in Example 7.2. [Figure 26] 7 depicts the dissolution profile over time of tablet D for the compound of formula (I), as further described in Example 7.2. [Figure 27] 7 shows the X-ray powder diffraction patterns of tablet A before and after 12 months of storage under the conditions described in Example 7.3. [Figure 28] 7 shows the X-ray powder diffraction patterns of tablet B before and after 12 months of storage under the conditions described in Example 7.3. [Figure 29]7 shows the X-ray powder diffraction patterns of tablet D before and after 12 months of storage under the conditions described in Example 7.3. DETAILED DESCRIPTION OF THE INVENTION

[0014] As used herein, the term "amorphous solid dispersion" refers to a solid dispersion comprising an amorphous compound of formula (I) and a polymer matrix as defined herein.

[0015] As used herein, the term "solid dispersion" refers to a solid-state system containing at least two components, one component dispersed throughout the other component.

[0016] As used herein, "amorphous compound of Formula (I)" means a compound of Formula (I) that is essentially free of crystalline form. The amorphous nature of a solid is generally determined by X-ray powder diffraction (XRPD). The X-ray powder diffraction pattern of an amorphous solid generally exhibits a broad halo without sharp peaks, as is apparent to those skilled in the art using conventional XRPD techniques.

[0017] "Essentially free of crystalline form", with respect to a compound of formula (I), means comprising at least 95%, suitably at least about 98%, and ideally at least about 99% of the compound of formula (I) in amorphous form, as measured by X-ray powder diffraction by conventional methods as further described herein.

[0018] The term "polymer matrix" as used herein refers to any one of the polymers selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (also known as HPCMAS), copolymer N-vinyl-2-pyrrolidone / vinyl acetate (also known as PPVVA), polyvinylpyrrolidone (also known as PVP), hypromellose phthalate (also known as HPMCP), and hypromellose (also known as HPMC). These polymer matrices are generally commercially available and are available in different physical / chemical grade types, as will be apparent from the experimental section.

[0019] In a first aspect, the present invention provides a solid dispersion comprising an amorphous compound of formula (I) and hydroxypropyl methylcellulose acetate succinate.

[0020] In a second aspect, the present invention provides a solid dispersion comprising an amorphous compound of formula (I) and the copolymer N-vinyl-2-pyrrolidone / vinyl acetate.

[0021] In a third aspect, the present invention provides a solid dispersion comprising an amorphous compound of formula (I) and polyvinylpyrrolidone.

[0022] In a fourth aspect, the present invention provides a solid dispersion comprising an amorphous compound of formula (I) and hypromellose phthalate.

[0023] In a fifth aspect, the present invention provides a solid dispersion comprising an amorphous compound of formula (I) and hypromellose.

[0024] The amorphous solid dispersion according to the present invention comprises about 30% to about 60% by weight of the amorphous compound of formula (I) based on the total weight of the amorphous solid dispersion, hereinafter referred to as "wt %."

[0025] In a first embodiment according to the present invention, the solid amorphous dispersion comprises about 30% by weight of the amorphous compound of formula (I).

[0026] In a second embodiment according to the present invention, the solid amorphous dispersion comprises about 40% by weight of the amorphous compound of formula (I).

[0027] In a third embodiment according to the present invention, the solid amorphous dispersion comprises about 50% by weight of the amorphous compound of formula (I).

[0028] In a fourth embodiment according to the present invention, the solid amorphous dispersion comprises about 60% by weight of the amorphous compound of formula (I).

[0029] Specific examples of amorphous solid dispersions according to the present invention include an amorphous solid dispersion comprising about 30% by weight of a compound of formula (I) and hydroxypropyl methylcellulose acetate succinate; an amorphous solid dispersion comprising about 40% by weight of a compound of formula (I) and hydroxypropyl methylcellulose acetate succinate; an amorphous solid dispersion comprising about 50% by weight of a compound of formula (I) and hydroxypropyl methylcellulose acetate succinate; an amorphous solid dispersion comprising about 60% by weight of a compound of formula (I) and hydroxypropyl methylcellulose acetate succinate; an amorphous solid dispersion comprising about 40% by weight of a compound of formula (I) and hypromellose; an amorphous solid dispersion comprising about 50% by weight of the compound of formula (I) and hypromellose; an amorphous solid dispersion comprising about 40% by weight of the compound of formula (I) and hypromellose phthalate; an amorphous solid dispersion comprising about 50% by weight of the compound of formula (I) and hypromellose phthalate; an amorphous solid dispersion comprising about 40% by weight of the compound of formula (I) and polyvinylpyrrolidone; an amorphous solid dispersion comprising about 50% by weight of the compound of formula (I) and polyvinylpyrrolidone; and an amorphous solid dispersion comprising about 40% by weight of the compound of formula (I) and the copolymer N-vinyl-2-pyrrolidone / vinyl acetate.

[0030] The amorphous solid dispersion according to the present invention can be prepared, for example, by spray drying. Typically, the monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, hereinafter referred to as the compound of formula (Ia), and the polymer matrix as defined herein are dissolved in a suitable solvent or a mixture of suitable solvents to form a feed solution, and then the feed solution is spray-dried to form the amorphous solid dispersion as a powder. Spray drying is a process well known to those skilled in the art for preparing amorphous solid dispersions.

[0031] The spray drying process according to the present invention is typically carried out continuously and comprises the following steps: (i) preparing a feed solution in which the compound of formula (Ia) and a carrier are dissolved in an organic solvent; (ii) conveying the feed solution through an atomizer to a drying chamber; (iii) contacting the droplets formed in step (ii) with a hot drying gas; (iv) evaporating the solvent; and (v) separating the dry solid particles from the drying gas.

[0032] Suitable solvents for the spray drying process according to the present invention are dichloromethane (DCM), methanol, ethanol, ethyl acetate, acetone, water or mixtures thereof. A particular solvent used according to the present invention is a mixture of dichloromethane and methanol, which is further described in the examples.

[0033] Atomization is generally accomplished by conventional means, for example, by feeding the solution through a nozzle at a pressure of from about 0.5 bar to about 2.5 bar, ideally from about 1.00 bar to about 2.5 bar.

[0034] The hot drying gas used in the drying chamber may be selected from air, nitrogen-enriched air, or argon. The temperature of the hot drying gas is generally between about 50°C and about 120°C, suitably between about 60°C and 120°C, resulting in an outlet temperature of between about 40°C and about 65°C.

[0035] The solid particles obtained after step (v) may be further dried by conventional means at a temperature of about 25°C to about 50°C, either at atmospheric or reduced pressure.

[0036] Alternatively, the amorphous solid dispersion may be prepared by a process involving hot melt extrusion. The hot melt extrusion process generally involves: i) feeding a system containing a powder mixture of the material to be extruded, in this case a compound of Formula (Ia) and a polymer matrix, in a continuous flow or controlled manner; ii) a conveying section consisting of a barrel and a screw for transporting, melting, and homogeneously mixing the fed blend; iii) shaping the melt into the desired form, including a sheet, film, or strand die; iv) further downstream processing steps including cooling, optionally pelletizing milling, and recovery of the resulting amorphous solid dispersion.

[0037] Hot melt extrusion processes are generally carried out at barrel temperatures above 100°C, suitably above 150°C.

[0038] Thus, in another aspect, the present invention provides a process for preparing an amorphous solid dispersion of a compound of formula (I) by spray drying or hot melt extrusion.

[0039] The amorphous solid dispersions of the present invention, as described hereinabove and in the Examples, have been characterized by the XRPDs shown in Figures 1-4 and 9-19.

[0040] Furthermore, the glass transition temperature (Tg) of the amorphous solid dispersion according to the present invention was measured by modulated differential scanning calorimetry, as further described in Table 3 of the Examples, according to methods familiar to those skilled in the art. Tg is considered the temperature at which an amorphous solid apparently transitions from a glassy solid state to a supercooled liquid upon heating (see A. Newman and G. Zografi in AAPS PharmSciTech (2020) 21:26). Tg provides an indication of the miscibility of the amorphous compound of formula (I) with the polymer matrix. When a single Tg or a narrow range of Tg is measured, this indicates that the amorphous solid dispersion is homogeneous. This state is also referred to as a glassy solution. Furthermore, the higher the Tg, the more the amorphous solid dispersion has reduced molecular mobility and therefore remains homogeneous over time, which is an indication of its stability.

[0041] The solid amorphous dispersions according to the present invention will generally have a Tg of above about 80°C, more usually above 100°C, suitably above about 105°C, ideally above about 110°C, very suitably above about 115°C, and especially above about 120°C.

[0042] Amorphous solid dispersions according to the present invention generally have a measured Tg region, as explained above, that is about 5° C. or less.

[0043] Thus, the amorphous solid dispersions according to the present invention are miscible and stable.

[0044] Additionally, the stability of some of the amorphous solid dispersions according to the present invention has been tested over time at room temperature as shown in Figures 5 and 6 and further detailed in the Examples, which show that these amorphous solid dispersions are stable at room temperature for at least 10 months.

[0045] The amorphous solid dispersion of the compound of formula (I) according to the present invention is significantly more soluble than the monohydrate crystalline form of the compound of formula (I), herein referred to as the compound of formula (Ia).This improved solubility is particularly advantageous when pharmaceutical compositions need to be prepared for oral administration, since it can achieve higher bioavailability.This can also allow for a reduction in dosage, and therefore a reduction in the tablet size used, when a solid formulation is desired.

[0046] Example Table 4 shows comparative solubility data between ASD1-ASD4 and the compound of formula (Ia) in different media, showing a minimum 30-fold increase in solubility of the amorphous solid dispersions, and a maximum of over 100-fold increase.

[0047] The amorphous solid dispersions according to the present invention can be further combined with pharmaceutically acceptable excipients such as diluents, binders, disintegrants, lubricants, glidants or carriers to form suitable pharmaceutical compositions.

[0048] Pharmaceutical compositions comprising the amorphous solid dispersions according to the present invention can be administered, for example, orally, parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally, by inhalation or intranasally.

[0049] Suitable diluents and carriers can take a wide variety of forms depending on the desired route of administration, for example oral, rectal, parenteral, or intranasal.

[0050] Pharmaceutical compositions suitable for oral administration may be solid or liquid and may, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gum, or the like.

[0051] Pharmaceutical compositions according to the present invention are generally prepared by mixing the amorphous solid dispersion with an inert diluent or non-toxic pharmaceutically acceptable carrier, such as starch, lactose, mannitol, or dicalcium phosphate, according to conventional pharmaceutical compounding techniques known to those skilled in the art. These pharmaceutical compositions may also contain binders such as microcrystalline cellulose, gum tragacanth, or gelatin, disintegrants such as croscarmellose sodium or crospovidone alginate, lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or coloring or flavoring agents such as peppermint or methyl salicylate, and coating agents such as Opadry™ (I, II, AMBII, QX, or EZ).

[0052] In certain embodiments, a pharmaceutical composition according to the present invention is prepared by mixing any one of the solid amorphous dispersions according to the present invention with excipients as further detailed in the process steps described in Example 7.1.

[0053] The amount of amorphous solid dispersion in a pharmaceutical composition can fall within a wide range of concentrations and depends on various factors such as the patient's sex, age, weight, and condition, as well as the method of administration. Thus, the amount of amorphous solid dispersion for oral administration is generally about 0.5% to about 85% by weight, suitably about 20% to about 60% by weight, based on the total weight of the composition.

[0054] In certain embodiments, the present invention relates to a solid pharmaceutical composition comprising about 20% to about 60% by weight of an amorphous solid dispersion relative to the total weight of the uncoated tablet in combination with any of the excipients described above.

[0055] In particular, the present invention relates to a tablet composition comprising: compared to the total weight of the uncoated tablet. about 20% to about 60% by weight of an amorphous solid dispersion; about 10% to about 50% by weight lactose monohydrate; about 10% to about 50% by weight microcrystalline cellulose; about 1% to about 5% by weight of croscarmellose sodium; about 0.1% to about 2% by weight of colloidal anhydrous silica; and about 0.1% to about 5% by weight of magnesium stearate Includes.

[0056] These excipients are generally mixed with the amorphous solid dispersion through one or more blend phases and optionally a diluent phase, as further described in Example 7.1.

[0057] In one embodiment, the pharmaceutical composition comprises about 25% by weight of the amorphous solid dispersion, hi another embodiment, the pharmaceutical composition comprises about 50% by weight of the amorphous solid dispersion.

[0058] In a first embodiment, the pharmaceutical composition comprises about 47.15% by weight of lactose monohydrate. In a second embodiment, the pharmaceutical composition comprises about 27.5% by weight of lactose monohydrate.

[0059] In a first embodiment, the pharmaceutical composition comprises about 25.95% by weight of microcrystalline cellulose. In a second embodiment, the pharmaceutical composition comprises about 18.7% by weight of microcrystalline cellulose.

[0060] In a first embodiment, the pharmaceutical composition comprises about 1.35% by weight of croscarmellose sodium. In a second embodiment, the pharmaceutical composition comprises about 2.7% by weight of croscarmellose sodium.

[0061] In a first embodiment, the pharmaceutical composition comprises about 0.25% by weight of colloidal anhydrous silica. In a second embodiment, the pharmaceutical composition comprises about 0.50% by weight of colloidal anhydrous silica.

[0062] In a first embodiment, the pharmaceutical composition comprises about 0.30% by weight of magnesium stearate. In a second embodiment, the pharmaceutical composition comprises about 0.60% by weight of magnesium stearate.

[0063] In certain embodiments, the amorphous solid dispersion is ASD1.

[0064] The present invention also contemplates compositions that can release the active substance in a controlled manner. Pharmaceutical compositions that can be used for parenteral administration are in conventional forms such as aqueous or oily solutions or suspensions, which are generally contained in ampoules, disposable syringes, glass or plastic vials or injection containers.

[0065] In addition to the amorphous solid dispersions, these solutions or suspensions may optionally also contain sterile diluents such as water for injection, saline, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, antifoaming agents, chelating agents such as ethylenediamine-tetraacetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting osmotic pressure such as sodium chloride or dextrose, as well as thickeners such as hydroxypropylcellulose (HPC-SSL), hypromellose derivatives (HPMC) and finally stabilizers such as PPVVA, PVP and polyvinyl alcohol (PVA).

[0066] These pharmaceutical forms are prepared using methods routinely used by pharmacists.

[0067] International Patent Application No. PCT / EP2020 / 068183, published as WO 2021 / 001288, describes that compounds of formula (I) may be useful for treating cognitive and negative symptoms in diseases and / or disorders in which D1 receptors play a role, in particular schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, anorexia, traumatic spinal cord injury or neuropathic pain.

[0068] Thus, in a further aspect, the present invention provides an amorphous solid dispersion as described herein or a pharmaceutical composition thereof for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, anorexia, traumatic spinal cord injury or neuropathic pain.

[0069] In a particular aspect, the present invention provides an amorphous solid dispersion as defined above or a pharmaceutical composition thereof for use in the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

[0070] The present invention also provides the use of an amorphous solid dispersion as described herein or a pharmaceutical composition thereof for the manufacture of a medicament for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, anorexia, traumatic spinal cord injury or neuropathic pain.

[0071] In a particular aspect, the present invention provides the use of an amorphous solid dispersion as defined above or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia.

[0072] The present invention also provides a method for the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, amotivation, traumatic spinal cord injury or neuropathic pain, which method comprises administering to a patient in need of such treatment an effective amount of an amorphous solid dispersion as described herein, or a pharmaceutical composition thereof.

[0073] In certain aspects, the present invention provides methods for the treatment and / or prevention of cognitive and negative symptoms in Parkinson's disease and other movement disorders, Alzheimer's disease, or schizophrenia, comprising administering to a patient in need of such treatment an effective amount of an amorphous solid dispersion or pharmaceutical composition thereof as described herein.

[0074] example Abbreviations / Replicate Reagents ACN: acetonitrile Brine: saturated aqueous sodium chloride solution nBu: n-butyl tBu: tert-butyl Cellulose, microcrystalline: Avicel PH-105&PH-200 (product name) Croscarmellose sodium: Ac-Di-Sol (product name) cAMP: cyclic adenosine monophosphate DCM: dichloromethane DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide mDSC: Modulated Differential Scanning Calorimetry ES + : Electrospray positive ionization Et: Ethyl EtOH: ethanol Et2O: Diethyl ether EtOAc: ethyl acetate h: time HPLC: High-Performance Liquid Chromatography HTRF: Homogeneous time-resolved fluorescence HPCMAS-L: Hydroxypropyl methylcellulose acetate succinate L grade HPMCAS-M: Hydroxypropyl methylcellulose acetate succinate M grade HPMC E3LV: Hypromellose E3LV grade HPMC 15LV: Hypromellose 15LV grade (trade name Affinisol) HPMC 100LV: Hypromellose 100LV grade (trade name Affinisol) HPMCP HP-55: Hypromellose phthalate HP55 grade lactose monohydrate: FlowLac90 (trade name) LCMS: Liquid Chromatography Mass Spectrometry Magnesium stearate: HyQual2257 (trade name) MeOH: Methanol min.:minutes NCS: N-chlorosuccinimide NMR: nuclear magnetic resonance iPrOH: Isopropanol PVPVA 64: Copolymer N-vinyl-2-pyrrolidone / vinyl acetate PVP 17PF: Polyvinylpyrrolidone 17PF grade rt: room temperature SFC: Supercritical Fluid Chromatography Silica, colloidal anhydrous: Cab-O-Sil M-5P (trade name) TEA: Triethylamine THF: tetrahydrofuran TLC: Thin Layer Chromatography Tg: glass transition temperature XRPD: X-ray powder diffraction IUPAC names were determined using Biovia Draw 16.1.

[0075] 1.Analysis method All reactions involving air- or moisture-sensitive reagents were carried out under a nitrogen or argon atmosphere using dry solvents and glassware. Commercially available solvents and reagents were generally used without further purification, including anhydrous solvents where appropriate (generally Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). Reactions were generally followed by thin-layer chromatography, HPLC, or mass spectrometry according to conventional methods known to those skilled in the art.

[0076] The crude material could be purified by normal phase chromatography, (acidic or basic) reverse phase chromatography, chiral separation or recrystallization.

[0077] Products were generally dried under vacuum before final analysis and biological testing.

[0078] All NMR spectra were obtained at 250 MHz, 300 MHz, 400 MHz or 500 MHz.

[0079] Compounds were tested in DMSO-d, CDCl, or MeOH-d solutions at a probe temperature of 300 K and a concentration of 10 mg / mL. The instrument was locked to the deuterium signal of DMSO-d, CDCl, or CDOD. Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) as an internal standard.

[0080] 2. Preparation of the monohydrate crystalline form of 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (Ia) The compound of formula (Ia) was prepared by applying the same synthetic method as described in Example 2 of co-pending International Patent Application WO2021 / 001288, which is incorporated herein by reference.

[0081] The following recrystallization procedure was also applied as an alternative to the recrystallization procedure disclosed in section 2.8.

[0082] Recrystallization is performed on 5.00 g of crude material solubilized in 240 ml of dimethyl sulfoxide. The solution is heated to 40°C and then filtered on P3 sintered glass. The reactor and filter are rinsed with 35 ml of dimethyl sulfoxide. The filtrate is transferred to a clean reactor and heated to 85°C. 110 ml of water is slowly charged over 30 minutes. 250 mg of compound (Ia) (0.5% w / w, monohydrate form) is then added to the reaction mixture. The mixture is stirred at 85°C for 2 hours and 30 minutes, and the crystalline material is removed from the solution, after which it is slowly cooled to 20°C over 12 hours. The suspension is filtered, and the filter cake is rinsed successively with several portions of water, followed by 150 ml of ethyl acetate. The filter cake is dried under vacuum at 50-60°C. 46.9 g of compound (Ia) is obtained as an off-white powder. Yield=94% 1 H NMR(400 MHz,DMSO-d6)δ 7.65(dd,J=9.0,2.2 Hz,1H),7.52(dd,J=9.0,2.1 Hz,1H),7.37(ddd,J=19.6,7.6,1.7 Hz,1H),7.25-7.03(m,2H),5.30(q,J=6.5 Hz,0.3H),5.16-4.99(m,1.7H),4.99-4.84(m,0.7H),4.63-4.30(m,3.3H),4.17-3.93(m,4H),3.28(dt,J=10.5,5.1 Hz,1.3H),3.10-2.85(m,1.7H),1.56(dd,J=13.2,6.9 Hz,6.7H),1.24(d,J=6.5 Hz,2.3H).

[0083] Preparation and characterization of amorphous solid dispersions of 3.2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone 3.1. Spray drying procedure Compound (Ia) and the carrier are dissolved in organic solvent(s) and spray-dried to obtain the different solid dispersions described below in paragraph 3.1.a and in Table 1. The polymer matrices used are generally commercially available and can be obtained in different grades of quality.

[0084] Different types of spray dryers can be used. The spray dryer used in this procedure is ProCept 4M8-TriX (ProCept, Belgium).

[0085] 3.1.a. Synthesis of Amorphous Solid Dispersion 1 (ASD1) Approximately 40 g of the compound of formula (Ia) and approximately 60 g of commercially available HPCMAS-L, corresponding to a weight ratio of approximately 40 / 60 wt%, are completely dissolved in a 76 / 24 wt% mixture of dichloromethane and methanol to reach a total solids content of approximately 5% (w / w). The feed solution is then pumped through a two-fluid nozzle at a rate of 18 g / min under a pressure of 1.5 bar and atomized into fine droplets. The solvent is evaporated by a cocurrent dry air stream set at an inlet temperature of 65 °C. The atomization and drying parameters are adjusted to achieve an outlet temperature of 40-45 °C. Once evaporated, the dried particles are collected through a cyclone. The collected wet material is stored in a vacuum oven at a temperature of 25° C. for an additional 12 hours to obtain approximately 85 g of the desired solid dispersion of amorphous 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone, designated ASD1. Yield = approximately 85% (material recovered after secondary drying / material dissolved in feed solution).

[0086] Other amorphous solid dispersions can be prepared in a similar manner using the amounts of the compound of formula (Ia) and polymer matrix summarized in Table 1 below. [Table 1]

[0087] 3.2.Hot Melt Extrusion Procedure Approximately 10 g of a powder mixture of compound (Ia) and polymer matrix was prepared in the weight percentages listed in Table 2. For example, when 40 wt% (Ia) is shown, this represents approximately 4.0 g of compound (Ia) and approximately 6.0 g of polymer matrix.

[0088] The polymer matrix used is generally commercially available and can be obtained in different grades. Compound (Ia) and the polymer matrix were blended for 5 minutes in a three-dimensional shaker system TURBULA™ (WAB). The preblend was then sieved through a #25 mesh (approximately 700 μm) screen and blended for an additional 5 minutes in the TURBULA™ system. The premixed powder was then manually fed into a bench-scale hot melt extruder (Thermo Scientific HAAKE™ MiniCTW Micro Conical Twin Screw Compounder, ThermoFisher) operating in a counter-rotating screw configuration. The barrel temperature was fixed at 160°C, and the screw speed was set at 200 rpm. A forced feeder was used to fill the barrel with a fixed auger speed of 500 rpm. After cooling to ambient temperature, the extrudate was collected. After a single pass in the barrel, visual observations were made of each extrudate. If the extrudate did not appear transparent, the material was recirculated in the barrel for an additional 2 minutes and extruded. After extrusion, the material was milled in a small burr-type mill system for 1-2 minutes while passing through a #60 mesh (approximately 250 μm) screen. The milled extrudate was sieved through a 250 μm sieve, and the different fractions were kept separate. [Table 2]

[0089] 3.3. X-ray powder diffraction (XRPD) of ASD1-ASD17 The amorphous solid dispersions ASD1 to ASD17 obtained by spray drying and hot melt extrusion, respectively, as described herein have been characterized by XRPD according to the following general procedure.

[0090] X-ray powder patterns for ASD1-ASD15 were obtained in reflection geometry using a PANalytical Empyrean Series 2 X-ray powder diffractometer with CuKα radiation equipped with a Bragg-Brentano HD optical module for the incident beam path and a PIXel 3D detector. Data were recorded using data acquisition software. The tube voltage during measurements was 45 kV and the amperage was 40 mA. Samples placed in either a flat zero-background, zero-background cup, or back-loading sample holder were analyzed at scan rates of 0.2° / min to 2.1° / min at 4, 5, and 30° 2θ. Data were processed using Data Viewer or HighScore Plus.

[0091] X-ray powder patterns for ASD16 and ASD17 were obtained using a Rigaku Miniflex 6G X-ray diffractometer using CuKα radiation in reflection geometry. The tube voltage was 40 kV and the amperage was 15 mA. Samples placed in either the zero-background cup or the zero-background low-volume cup were analyzed from 3 to 30° 2θ at a scan rate of 0.9° / min. Data were processed using Data Viewer or HighScore Plus.

[0092] Figures 1-4, 9-19, 21, and 22 show the XPRD patterns of ASD1-ASD17, which exhibit the typical amorphous solid halo. Note that the peaks appearing in the patterns of ASD7 and ASD12 are not due to the presence of the crystalline form of the compound of formula (I), but rather to some impurities originating from the polymer matrix.

[0093] 3.4. Differential Scanning Calorimetry (DSC) of Solid Dispersions of Amorphous 2-(3,5-Dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(Hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethenone The phase behavior and thermal properties of ASD1-15 obtained in paragraphs 3.1 and 3.2 were analyzed by modulated differential scanning calorimeter (mDSC) using a TA Instruments Q1000 calorimeter (TA Instruments, Leatherhead, UK). The chamber was purged with dry nitrogen at a flow rate of 50 mL / min. Indium and sapphire disks were used to measure temperature / enthalpy and heat capacity, respectively. The powders were analyzed in non-hermetic standard aluminum pans (TA Instruments, Leatherhead, UK). In a typical mDSC analysis, the sample was heated from 0 °C to 250 °C at 2 °C / min with ±1 °C adjustment for 40–60 s. Data were processed using Universal Analysis 2000 software (TA Instruments, Leatherhead, UK). The glass temperature (Tg) was reported as the inflection point of the process change observed in the reversing heat flow signal, and crystallization and melting events were recorded in the non-reversing and total heat flow. [Table 3]

[0094] 3.5. Stability of ASD1, ASD2, ASD3, and ASD4 The XRPDs of ASD1 to ASD4 shown in Figures 1 to 4 were obtained at t=0.

[0095] Furthermore, the XRPD of ASD1 was obtained after 12 months at 25°C and 60% relative humidity, and the resulting pattern is shown in Figure 5 .

[0096] XRPD of ASD2, ASD3, and ASD4 were also collected after 10 months at room temperature in the presence of silica gel as a desiccant, and the resulting patterns are shown in Figure 6.

[0097] These studies show that ASD1-ASD4 are all stable for at least 10 months.

[0098] 4. Comparative solubility of solid dispersions of amorphous 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone with the compound of formula (Ia) The solubility of each of the compound of formula (Ia) and ASD1 was measured in different media using the shake flask method. Excess solid (corresponding to a concentration of 5 mg / mL of the compound of formula (I)) was suspended in 5 mL of buffer / biorelevant medium as specified in Table 4 and incubated in a sealed glass vial (10 mL) at both room temperature and 37 °C in a climate chamber equipped with a rotating mixer for 24 hours. The 24-hour time point was considered to be the time when solubility was reached, at which point the suspension was filtered through a 0.45 μm Ultrafree filter (Merck Millipore) and the drug content was measured by HPLC. The solubility of compound (Ia) and ASD1 was measured three times (n = 3). If necessary, the filtrate was diluted with an appropriate organic solvent to prevent drug precipitation.

[0099] Table 4 below shows the solubility of compound (Ia) compared to that of ASD1 in various media. These media are phosphate buffer, FasSGF, FASSIF-V2, and FeSSIF-V2, respectively. FasSG is gastric juice in the fasted state. FasSGF is prepared at pH 1.6 and contains 0.08 mM taurocholate, 0.02 mM phospholipids, 34 mM sodium, and 59 mM chloride. FaSSIF-V2 and FeSSIF-V2 are biorelevant media in the fasted and fed states, respectively. FaSSIF-V2 is prepared at pH 6.5 and contains 3 mM taurocholate, 0.2 mM phospholipids, 106 mM sodium, 69 mM chloride, and 19 mM maleic acid. FeSSIF-V2 is prepared at pH 5.8 and contains 10 mM taurocholate, 2 mM phospholipids, 0.8 mM oleate, 5 mM glycerol monooleate, 218 mM sodium, 125 mM chloride, and 55 mM maleic acid. [Table 4]

[0100] The results obtained above show that a minimum of a 30-fold increase in solubility and a maximum of more than a 100-fold increase in solubility for ASD1 can be obtained compared to the compound of formula (Ia).

[0101] 5. Dissolution Profiles of ASD1 and Compound of Formula (Ia) 5.1. General Procedure Dissolution profiles were measured in a USP apparatus type 2 (Distek 2100C Dissolution Apparatus) at 37° C. The dynamic dissolution test involved first dissolution in simulated gastric medium (0.1 N HCl) for 30 minutes to achieve a concentration equivalent to that of the compound of formula (I) of 1 mg / mL, followed by dissolution in FaSSIF-V2 for 180 minutes to achieve a concentration equivalent to that of the compound of formula (I) of 0.5 mg / mL.

[0102] 5.2. ASD1 lysis 125 mg of ASD1 was weighed and placed in a 100 mL container. Then, 50 mL of simulated gastric medium (0.1 N HCl) was added to the container, and the paddle speed was fixed at 100 rpm. After 30 minutes, an equal volume (50 mL) of fasted-state biorelevant medium was added to the container to obtain the composition of FaSSIF-V2. Dissolution was performed in triplicate (n=3). At each time point, the suspension was filtered through a 0.45 μm Ultrafree filter (Merck Millipore), and the content of compound of formula (I) was measured by HPLC. The filtrate was then diluted with an appropriate organic solvent. The dissolution profile of ASD1 is shown in Figure 7.

[0103] 5.3. Dissolution Profile of Compound (Ia) FIG. 8 shows the dissolution profile of compound (Ia) carried out under conditions similar to those described above.

[0104] From a comparison of Figures 7 and 8, it can be inferred that ASD1 dissolves rapidly in gastric media compared to compound (Ia) and remains highly soluble for several hours, whereas the solubility of compound (Ia) decreases to very low levels in gastric media during the same period. Overall, ASD1 was found to generate and maintain supersaturation over the duration of the experiment.

[0105] This confirms that the amorphous solid dispersions according to the invention, in particular ASD1, have an improved solubility profile and therefore advantageous properties compared to the compound of formula (Ia).

[0106] 6. In vivo bioavailability of ASD1 liquid suspension 6.1.ASD1 liquid suspension The formulation excipient used for the following suspensions is a mixture containing 1% (w / v) hydroxypropyl cellulose grade SSL, 10% (w / v) PVPVA, and 0.1% (w / v) Antifoam 1510 USA in water at pH 3.0 containing 50 mM citrate buffer.

[0107] First, a pH 3.0 solution of 50 mM citrate buffer was prepared in water. Hydroxypropyl cellulose grade SSL, PVPVA, and Antifoam 1510 US were dissolved sequentially in the freshly prepared citrate buffer and stirred (magnetic stirring) for 120 minutes.

[0108] 15.0 g of ASD1 was weighed and placed in a container. 88.8 g of the prepared excipient was added to ASD1 while manually mixing with a glass rod or stainless steel spatula. 88.8 g of additional excipient was then added, and the suspension was then stirred at 250 rpm for an additional 30 minutes. The suspension was again stirred with a magnetic bar / stirrer for 15 minutes before and throughout administration to animals unless constant stirring was maintained.

[0109] 6.2. Dosing and Bioavailability Measurements Four groups of two male and two female dogs were treated with ASD1 in a suspension prepared according to Example 6.1 at doses of 10, 25 and 75 mg / kg / day, respectively, for 14 consecutive days.

[0110] Plasma samples were collected on days 1 and 14 at different time points post-dose: 1, 2, 4, 7, 12 and 24 hours post-dose.

[0111] Plasma concentrations of Compound (I) were quantified by LC / MS (liquid chromatography / mass spectrometry).

[0112] Area under the curve (AUC 24 ) was calculated using the log-lin interpolation rule from 0 to 24 hours on days 1 and 14. As shown in Figure 20, this AUC 24 is divided by the administered dose and plotted as a function of dose.

[0113] Figure 20 shows the AUC 24 increased proportionally with the administered dose, thus indicating that ASD1 in suspension maintained the same level of bioavailability when the dose was increased from 10 to 75 mg / kg.

[0114] 7. Tablets containing ASD 7.1. Preparation of Tablets and Tablet Compositions Containing Amorphous Solid Dispersions The amorphous solid dispersion obtained according to Example 3 is formulated into tablets according to the following methods commonly known to those skilled in the art, following the general process steps described below. 1) Blend the amorphous solid dispersion with suitable excipients such as microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, anhydrous colloidal silica and magnesium stearate. 2) The blend obtained in step 1, referred to herein as Blend #1, is compressed by dry granulation and then milled. 3) The granules obtained in step 2 are further blended with suitable excipients such as microcrystalline cellulose, croscarmellose sodium and magnesium stearate. 4) The resulting blend from step 3 (hereafter referred to as Blend #2) is optionally diluted with microcrystalline cellulose and lactose monohydrate at a specific dosage strength and then compressed to obtain uncoated tablets. 5) Uncoated tablets are spray coated with a suitable coating such as Opadry™ (I, II, AMBII, QX, or EZ).

[0115] An example of a tablet obtained by applying the above process steps to ASD1 is constructed as follows: [Table 5] Coated tablets A, B, C and D further contain approximately 4, 4, 10 and 20 mg of Opadry AMB II 88 A180040 white, respectively.

[0116] 7.2. Dissolution Profiles of Tablets A, B, C, and D The dissolution profiles of coated tablets A, B, C, and D were measured according to the procedure described in Example 5 and are shown in Figures 23, 24, 25, and 26, respectively. Note that the number of tablets or the volume of dissolution medium can be adapted to reach the desired target concentration.

[0117] The results obtained for tablets A, B, C and D demonstrate that the amorphous solid dispersions and their corresponding solid formulations offer advantages in terms of solubility and dissolution rate compared to the monohydrate crystalline compound of formula (Ia).

[0118] 7.3. Stability of Tablets A, B, C and D Coated tablets A, B, and D packaged in high-density polyethylene bottles containing 2 g of silica gel desiccant in a screw-top cap were found to be stable after 12 months of storage at 25°C and 60% relative humidity.

[0119] Figures 27, 28 and 29 show the X-ray powder diffraction patterns of tablets A, B and D, respectively, before and after 12 months of storage under the conditions described herein above.

Claims

1. A solid dispersion of amorphous 2-(3,5-dichloro-1-methyl-indazol-4-yl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(1-hydroxy-1-methyl-ethyl)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethanone of formula (I) and a polymer matrix. 【Chemistry 1】

2. 2. The solid dispersion of claim 1, wherein the polymer matrix is ​​selected from the group consisting of hydroxypropyl methylcellulose acetate, copolymer N-vinyl-2-pyrrolidone / vinyl acetate, polyvinylpyrrolidone, hypromellose phthalate, and hypromellose.

3. 3. The solid dispersion of claim 2, wherein the polymer matrix is ​​hydroxypropyl methylcellulose acetate or a copolymer N-vinyl-2-pyrrolidone / vinyl acetate.

4. 10. The solid dispersion of claim 1, comprising about 30% to about 60% by weight of the amorphous compound of formula (I) relative to the total weight of the amorphous solid dispersion.

5. 5. The solid dispersion of claim 4, comprising about 40% by weight of the amorphous compound of formula (I) compared to the total weight of the amorphous solid dispersion.

6. 2. The solid dispersion of claim 1, having a glass transition temperature (Tg) greater than about 80°C.

7. 7. The solid dispersion of claim 6, having a glass transition temperature (Tg) greater than about 100°C.

8. 10. A method for preparing the solid dispersion of claim 1 by spray drying, comprising the steps of: (i) dissolving the compound of formula (Ia) and hydroxypropyl methylcellulose acetate, copolymer N-vinyl-2-pyrrolidone / vinyl acetate, polyvinylpyrrolidone, hypromellose phthalate or hypromellose in a solvent; (ii) conveying the resulting solution of step (i) into an atomization chamber; (iii) contacting the droplets formed as a result of step (ii) with a hot dry gas; (iv) evaporating the solvent; (v) Separating the resulting solid dispersion from the dry gas. A method for providing the above.

9. 10. A process for preparing the solid dispersion of claim 1 by hot melt extrusion, comprising: (i) mixing a compound of formula (Ia) with hydroxypropyl methylcellulose acetate, copolymer N-vinyl-2-pyrrolidone / vinyl acetate, polyvinylpyrrolidone, hypromellose phthalate or hypromellose; (ii) feeding the mixture obtained in step (i) into a hot melt extruder, the barrel and screw section of which continuously conveys the mixture at a temperature above 150°C until a melt is obtained; (iii) cooling the melt obtained in step (ii) to ambient temperature. A method for providing the above.

10. 10. A pharmaceutical composition comprising the solid dispersion of claim 1 in combination with one or more pharmaceutically acceptable excipients.

11. A pharmaceutical comprising the solid dispersion according to claim 1 in the form of a tablet, based on the total weight of the uncoated tablets, 20% to 60% by weight of an amorphous solid dispersion; 10% to 50% by weight of lactose monohydrate; 10% to 50% by weight of microcrystalline cellulose; 1% to 5% by weight of croscarmellose sodium; 0.1% to 2% by weight of colloidal anhydrous silica; and 0.1% to 5% by weight of magnesium stearate Pharmaceuticals, including:

12. 12. The solid dispersion according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 10 or 11 for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, anorexia, traumatic spinal cord injury or neuropathic pain.

13. 12. Use of the amorphous solid dispersion of any one of claims 1 to 7 or the pharmaceutical composition of claim 10 or 11 for the manufacture of a medicament for use in the treatment and / or prevention of cognitive and negative symptoms in schizophrenia, cognitive impairment associated with neuroleptic therapy, mild cognitive impairment (MCI), impulsivity, attention deficit hyperactivity disorder (ADHD), Parkinson's disease and other movement disorders, dystonia, Parkinsonism-related dementia, Huntington's disease, dementia with Lewy bodies, Alzheimer's disease, drug addiction, sleep disorders, anorexia, traumatic spinal cord injury or neuropathic pain.

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